5-(4-(haloalkoxy)phenyl) pyrimidine-2-amine compounds and compositions as kinase inhibitors

ABSTRACT

The invention provides compounds of formula (1) and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, as well as methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of c-kit, PDGFRα, PDGFRβ, CSF1R, AbI, BCR-AbI, CSK, JNK1, JNK2, p38, p70S6K, TGFβ, SRC, EGFR, trkB, FGFR3. Fes, Lck, Syk, RAF, MKK4, MKK6, SAPK2β, BRK, Fms, KDR, c-rapor b-raf kinases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 U.S. national phase application ofinternational application number PCT/US2008/073573 filed 19 Aug. 2008,which claims the benefit of U.S. provisional patent application Ser. No.60/957,260, filed 22 Aug. 2007. The full disclosure of theseapplications is incorporated herein by reference in their entirety andfor all purposes.

TECHNICAL FIELD

The invention relates to protein kinase inhibitors, and methods of usingsuch compounds. More particularly, the invention relates to c-kit andPDGFR inhibitors, and uses thereof for the treatment and prevention ofc-kit and PDGFR mediated disorders.

BACKGROUND ART

The protein kinases represent a large family of proteins, which play acentral role in the regulation of a wide variety of cellular processesand maintaining control over cellular function. A partial, non-limiting,list of these kinases include: receptor tyrosine kinases such asplatelet-derived growth factor receptor kinase (PDGFR), the receptorkinase for stem cell factor, c-kit, the nerve growth factor receptor,trkB, and the fibroblast growth factor receptor, FGFR3; non-receptortyrosine kinases such Abl and the fusion kinase BCR-Abl, Fes, Lck andSyk; and serine/threonine kinases such as b-RAF, MAP kinases (e.g.,MKK6) and SAPK2β. Aberrant kinase activity has been observed in manydisease states including benign and malignant proliferative disorders aswell as diseases resulting from inappropriate activation of the immuneand nervous systems.

DISCLOSURE OF THE INVENTION

The invention provides compounds and pharmaceutical compositionsthereof, which may be useful as protein kinase inhibitors.

In one aspect, the present invention provides compounds of Formula (1):

-   -   or a pharmaceutically acceptable salt thereof;    -   R¹ is a haloalkyl having 1-6 fluorine atoms;    -   R² is C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which        may be optionally substituted with halo, amino or hydroxyl        groups; halo, cyano, nitro, (CR₂)_(k)OR⁷, (CR₂)_(k)O(CR₂)₁₋₄R⁷,        (CR₂)_(k)SR⁷, (CR₂)_(k)NR⁹R¹⁰, (CR₂)_(k)C(O)O₀₋₁R⁷, OC(O)R⁷,        (CR₂)_(k)C(S)R⁷, (CR₂)_(k)C(O)NR⁹R¹⁰,        (CR₂)_(k)C(O)NR(CR₂)₀₋₆C(O)O₀₋₁R⁷, (CR₂)_(k)NRC(O)O₀₋₁R⁷,        (CR₂)_(k)S(O)₁₋₂NR⁹R¹⁰, (CR₂)_(k)S(O)₁₋₂R⁸, (CR₂)_(k)NRS(O)₁₋₂R⁸        or (CR₂)_(k)R⁶; or any two adjacent R² groups together may form        an optionally substituted 5-8 membered carbocyclic,        heterocyclic, aryl or heteroaryl ring;    -   R³ is -L-NR⁴R⁵, —X—NR—C(O)R⁸ or —X—NR—C(O)NR⁴R⁵ wherein L is        —X—C(O), —X—OC(O), —(CR₂)_(j), —SO₀₋₂(CR₂)_(j), —O(CR₂)₁₋₄, or

-   -    and X is (CR₂)_(j) or [C(R)(CR₂OR)];    -   R⁴, R⁵, R⁹ and R¹⁰ are independently H; C₁₋₆ alkyl, C₂₋₆ alkenyl        or C₂₋₆ alkynyl, each of which may be optionally substituted        with halo, amino, hydroxyl, alkoxy, cyano, carboxyl or R⁶;        (CR₂)_(k)CN, (CR₂)₁₋₆NR⁷R⁷, (CR₂)₁₋₆OR⁷, (CR₂)_(k)C(O)O₀₋₁R⁷,        (CR₂)_(k)C(O)NR⁷R⁷ or (CR₂)_(k)—R⁶;    -   R⁶ is an optionally substituted C₃₋₇ cycloalkyl, C₆ aryl, or a        5-6 membered heteroaryl or 5-7 membered heterocyclic ring;    -   R⁷ and R⁸ are independently (CR₂)_(k)—R⁶ or C₁₋₆ alkyl, C₂₋₆        alkenyl or C₂₋₆ alkynyl, each of which may be optionally        substituted with halo, amino, amido, hydroxyl, alkoxy, cyano,        carboxyl or R⁶; or R⁷ is H;    -   alternatively, R⁴ and R⁵ together with N in each NR⁴R⁵, R⁷ and        R⁷ together with N in NR⁷R⁷ or R⁹ and R¹⁰ together with N in        NR⁹R¹⁰ may form a 4-7 membered heterocyclic ring optionally        substituted with 1-3 R¹¹ groups;    -   R¹¹ is R⁸, (CR₂)_(k)—OR⁷, CO₂R⁷, (CR₂)_(k)—C(O)—(CR₂)_(k)—R⁸,        (CR₂)_(k)C(O)NR⁷R⁷, (CR₂)_(k)C(O)NR(CR₂)₀₋₆C(O)O₀₋₁R⁷,        (CR₂)_(k)NRC(O)O₀₋₁R⁷, (CR₂)_(k)S(O)₁₋₂NR⁷R⁷, (CR₂)_(k)S(O)₁₋₂R⁸        or (CR₂)_(k)NRS(O)₁₋₂R⁸;    -   each R is H or C₁₋₆alkyl;    -   each k is 0-6; and    -   j and m are independently 0-4;    -   provided R¹ is not trifluoromethoxy when R³ is C(O)NH₂,        C(O)NR¹²R¹³ or SO₂NH(CH₂)₂₋₃NR¹⁴R¹⁵; wherein R¹² and R¹³        together form piperazinyl and R¹⁴ and R¹⁵ together form        morpholinyl.

In the above Formula (1), R¹ may be OCHF₂, OCF₃, OCH₂CF₃, OCF₂CH₂ orOCH₂CF₃. In particular examples, R¹ is OCHF₂.

In some examples, R³ in the above Formula (1) is selected from the groupconsisting of

In other examples, R³ in the above Formula (1) is selected from thegroup consisting of

wherein R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)₁₋₆OH.

In yet other examples, R³ in the above Formula (1) is selected from thegroup consisting of

In one embodiment, the compounds have Formula (2A) or (2B):

-   -   wherein R⁴ and R⁵ together with N form a 5-6 membered        heterocyclic ring optionally containing NR¹⁶, O, S, ═O or a        double bond; wherein said heterocyclic ring is optionally        substituted with 1-2 R¹¹ groups;    -   R¹⁶ is H, R⁸, —(CR₂)₁₋₄CO₂R⁷, (CR₂)_(k)—C(O)—(CR₂)_(k)—R⁸,        (CR₂)_(k)C(O)NR⁷R⁷, (CR₂)_(k)C(O)NR(CR₂)₀₋₆C(O)O₀₋₁R⁷,        (CR₂)₁₋₄NRC(O)O₀₋₁R⁷, (CR₂)_(k)S(O)₁₋₂NR⁷R⁷, (CR₂)_(k)S(O)₁₋₂R⁸        or (CR₂)_(k)NRS(O)₁₋₂R⁸; and    -   R⁴, R⁵, R⁷, R⁸, R¹¹, R and k are as defined in Formula (1).

In the above Formula (2A) or (2B), R⁴ and R⁵ together with N in NR⁴R⁵may form an optionally substituted piperidinyl, piperazinyl ormorpholinyl. In some examples, L is —X—C(O), —(CR₂)₁₋₄ or —O(CR₂)₁₋₄;wherein X is (CR₂)₀₋₁ or [C(R)(CR₂OR)]. In other examples, L is(CR₂)₁₋₂.

In the above Formula (1), (2A) or (2B), R² if present, is halo, C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxy or CO₂R⁷ and R⁷ is H or C₁₋₆ alkyl.

In one embodiment, the present invention provides a compound selectedfrom the group consisting of:

-   N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine;-   N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine;-   1-(2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylic    acid;-   1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic    acid;-   1-(4-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic    acid;-   1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic    acid;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-methylpiperidine-2-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   (1S,2R,5R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)piperidine-2-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide;-   (R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-oxopiperidine-3-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-fluoropyridine-3-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1H-imidazole-5-carboxamide;-   N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide;-   (S)-N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-cyclopropyl-5-oxopyrrolidine-3-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-ethyl-6-oxopiperidine-3-carboxamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-N-(2-fluoroethyl)-3-hydroxypropanamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxypropyl)propanamide;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(4-hydroxycyclohexyl)propanamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4r)-4-hydroxycyclohexyl)propanamide;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1    s,4s)-4-hydroxycyclohexyl)propanamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(3-hydroxypiperidin-1-yl)propan-1-one;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxycyclopentyl)propanamide;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;-   2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)ethanone;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;-   (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;-   (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;-   2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(3-(trifluoromethyl)piperazin-1-yl)propan-1-one;-   2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1-yl)-3-hydroxypropan-1-one;-   N1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)piperidine-1,4-dicarboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methylpiperazine-1-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methanesulfonyl-piperazine-1-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-acetylpiperazine-1-carboxamide;-   1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)urea;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)morpholine-4-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)piperazine-1-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-4,7-diazaspiro[2.5]octane-7-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-4,7-diazaspiro[2.5]octane-7-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-(trifluoromethyl)piperazine-1-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-oxopiperazine-1-carboxamide;-   N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-3-oxopiperazine-1-carboxamide;-   1-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylic    acid;-   1-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic    acid;-   1-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic    acid;-   1-(2-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylic    acid;-   1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylic    acid;-   4-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-methylpiperazin-2-one;-   4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-(2-hydroxyethyl)piperazin-2-one;-   4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)piperazin-2-one;-   (4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)(3-(trifluoromethyl)piperazin-1-yl)methanone;-   Methyl    1-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate;-   1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-hydroxyphenethyl)piperidine-4-carboxylic    acid;-   1-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)ethyl)piperidine-4-carboxylic    acid;-   1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylbenzyl)piperidine-4-carboxylic    acid;-   1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-fluorobenzyl)piperidine-4-carboxylic    acid;-   1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-hydroxybenzyl)piperidine-4-carboxylic    acid;-   4-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-(piperidin-4-yl)piperazin-2-one;-   Isopropyl    4-(4-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-2-oxopiperazin-1-yl)piperidine-1-carboxylate;-   N-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-2-hydroxyethyl)tetrahydro-2H-pyran-4-carboxamide;-   N-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-2-hydroxyethyl)-1-ethyl-6-oxopiperidine-3-carboxamide;-   1-cyclopropyl-N-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-2-hydroxyethyl)-5-oxopyrrolidine-3-carboxamide;-   N-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-2-hydroxyethyl)-3,5-dimethylisoxazole-4-carboxamide;-   N-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-2-hydroxyethyl)isoxazole-5-carboxamide;-   N-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-2-hydroxyethyl)-2-(3-methylisoxazol-5-yl)acetamide;-   N-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-2-hydroxyethyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide;    and-   N3-(1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-2-hydroxyethyl)piperidine-1,3-dicarboxamide.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundhaving Formula (1), (2A) or (2B), and a pharmaceutically acceptableexcipient.

In yet another aspect, the present invention provides methods formodulating kinase activity, comprising administering to a system or asubject in need thereof, a therapeutically effective amount of compoundhaving Formula (1), (2A) or (2B), or pharmaceutically acceptable saltsor pharmaceutical compositions thereof, thereby modulating said kinaseactivity.

In one embodiment, the invention provides methods for modulating c-kit,PDGFRα, PDGFRβ, CSF1R, Abl, BCR-Abl, CSK, JNK1, JNK2, p38, p70S6K, TGFβ,SRC, EGFR, trkB, FGFR3, Fes, Lck, Syk, RAF, MKK4, MKK6, SAPK2β, BRK,Fms, KDR, c-raf or b-raf kinases. In particular embodiments, theinvention provides methods for modulating c-kit, PDGFRα or PDGFRβ; andmore particularly, the invention provides methods wherein a compoundhaving Formula (1), (2A) or (2B), or pharmaceutically acceptable saltsor pharmaceutical compositions thereof, may directly contact c-kit,PDGFRα or PDGFRβ in vitro or in vivo.

The present invention also provides methods for treating a disease orcondition wherein modulation of kinase activity can prevent, inhibit orameliorate the pathology and/or symptomology of the disease orcondition, comprising administering to a subject a therapeuticallyeffective amount of a compound having Formula (1), (2A) or (2B), orpharmaceutically acceptable salts or pharmaceutical compositionsthereof, and optionally in combination with a second therapeutic agent.Examples of therapeutic agents which may be used in combination with acompound of the invention include but are not limited to ananti-fibrotic agent, pirfenidone, tacrolimus, an anti-inflammatoryagent, a corticosteroid, a cromolyn, a leukotriene antagonist, an IgEblocker, a bronchodilator, a β₂-agonist, xanthines, an anticholinergic,or a chemotherapeutic agent. When administered with a second therapeuticagent, the compound of Formula (1), (2A) or (2B), or pharmaceuticallyacceptable salts or pharmaceutical compositions thereof may beadministered prior to, simultaneously with, or after the secondtherapeutic agent.

In one embodiment, the invention provides methods for treating a diseaseor condition modulated by c-kit, PDGFRα, PDGFRβ, CSF1R, Abl, BCR-Abl,CSK, JNK1, JNK2, p38, p70S6K, TGFβ, SRC, EGFR, trkB, FGFR3, Fes, Lck,Syk, RAF, MKK4, MKK6, SAPK2β, BRK, Fms, KDR, c-raf or b-raf kinases. Inparticular examples, the invention provides methods for treating adisease or condition modulated by PDGFRα, PDGFRβ or c-kit. In someexamples, the invention provides methods for treating a disease orcondition modulated by c-kit.

Examples of kinase mediated disease or conditions which may be mediatedusing the compounds and compositions of the invention include but arenot limited to a mast-cell associated disease, an allergy disorder,irritable bowel syndrome (IBS), a fibrotic disease, a neoplasticdisorder, an inflammatory disorder, an autoimmune disorder, agraft-versus-host disease, a metabolic syndrome, a CNS related disorder,a neurodegenerative disorder, a pain condition, a substance abusedisorder, a cancer, a cardiovascular disease, and a prion disease.

Examples of a mast cell associated disease which may be treated usingcompounds and compositions of the invention include but are not limitedto allergic disorders (including asthma and atopic dermatitis),urticaria, acne and Propionibacterium acnes, Fibrodysplasia ossificansprogressiva (FOP), inflammation and tissue destruction induced byexposure to chemical or biological weapons (such as anthrax andsulfur-mustard), cystic fibrosis; renal disease, inflammatory muscledisorders, HIV, type II diabetes, cerebral ischemia, mastocytosis, drugdependence and withdrawal symptoms, CNS disorders, preventing andminimizing hair loss, bacterial infections, interstitial cystitis,inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis,indeterminate colitis, and infectious colitis), tumor angiogenesis,autoimmune diseases, inflammatory diseases, multiple sclerosis (MS), andbone loss.

Examples of allergy disorders which may be treated using the compoundsand compositions of the invention include but are not limited to asthma,atopic dermatitis, allergic rhinitis, allergic sinusitis, anaphylacticsyndrome, urticaria, angioedema, allergic contact dermatitis, erythemanodosum, erythema multiforme, cutaneous necrotizing venulitis, insectbite skin inflammation, and blood sucking parasite infestation.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disordercharacterized by abdominal pain and altered bowel habit. Pain ischaracteristically relieved by defecation and may be associated withincrease or decrease in stool frequency, alterations in stoolconsistency, straining or urgency, a sensation of incomplete evacuation,passage of mucus or abdominal distention.

A fibrotic disease as used herein encompasses all conditions linked toor associated with the formation and deposition of extracellular matrixcomponents, particularly in the internal organs, including the kidneys,heart, lungs, liver, skin and joints. Examples of fibrotic diseaseswhich may be treated using the compounds and compositions of theinvention include but are not limited to scleroderma, pulmonaryfibrosis, idiopathic pulmonary fibrosis (IPF), primary pulmonaryhypertension (e.g., pulmonary arterial hypertension (PPAH)), liverfibrosis, renal fibrosis, cardiac fibrosis, cirrhosis in liver, bonemarrow fibrosis, hepatitis C(HCV) and nonalcoholic steatohepatitis(NASH).

Examples of neoplastic disorders which may be treated using thecompounds and compositions of the invention include but are not limitedto mastocytosis, gastrointestinal stromal tumor, small cell lung cancer,non-small cell lung cancer, acute myelocytic leukemia, acute lymphocyticleukemia, myelodyplastic syndrome, chronic myelogenous leukemia,colorectal carcinoma, gastric carcinoma, testicular cancer, glioblastomaand astrocytoma.

Examples of inflammatory disorders which may be treated using thecompounds and compositions of the invention include but are not limitedto rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis,osteoarthritis and gouty arthritis.

Examples of autoimmune disorders which may be treated using thecompounds and compositions of the invention include but are not limitedto multiple sclerosis, psoriasis, intestine inflammatory disease,inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease,rheumatoid arthritis, polyarthritis, local or systemic scleroderma,systemic lupus erythematosus, discoid lupus erythematosis, cutaneouslupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodularpanarteritis, autoimmune enteropathy and proliferativeglomerulonephritis.

Examples of graft-versus-host diseases which may be treated using thecompounds and compositions of the invention include but are not limitedto organ transplantation graft rejection, such as kidneytransplantation, pancreas transplantation, liver transplantation, hearttransplantation, lung transplantation, and bone marrow transplantation.

Examples of metabolic syndrome which may be treated using the compoundsand compositions of the invention include but are not limited to type Idiabetes, type II diabetes, and obesity.

Examples of CNS related disorders which may be treated using thecompounds and compositions of the invention include but are not limitedto depression, dysthymic disorder, cyclothymic disorder, anorexia,bulimia, premenstrual syndrome, post-menopause syndrome, mental slowing,loss of concentration, pessimistic worry, agitation, self-deprecationand decreased libido, an anxiety disorder, a psychiatric disorder andschizophrenia.

Examples of depression conditions which may be treated using thecompounds and compositions of the invention include but are not limitedto bipolar depression, severe or melancholic depression, atypicaldepression, refractory depression, and seasonal depression. Examples ofanxiety disorders which may be treated using the compounds andcompositions of the invention include but are not limited to anxietyassociated with hyperventilation and cardiac arrhythmias, phobicdisorders, obsessive-compulsive disorder, posttraumatic stress disorder,acute stress disorder, and generalized anxiety disorder. Examples ofpsychiatric disorders which may be treated using the compounds andcompositions of the invention include but are not limited to panicattacks, including psychosis, delusional disorders, conversiondisorders, phobias, mania, delirium, dissociative episodes includingdissociative amnesia, dissociative fugue and dissociative suicidalbehavior, self-neglect, violent or aggressive behavior, trauma,borderline personality, and acute psychosis such as schizophrenia,including paranoid schizophrenia, disorganized schizophrenia, catatonicschizophrenia, and undifferentiated schizophrenia.

Examples of neurodegenerative disorder which may be treated using thecompounds and compositions of the invention include but are not limitedto osteoarthritis, Alzheimer's disease, Parkinson's disease,Huntington's disease, the prion diseases, Motor Neuron Disease (MND),and Amyotrophic Lateral Sclerosis (ALS).

Examples of pain conditions which may be treated using the compounds andcompositions of the invention include but are not limited to acute pain,postoperative pain, chronic pain, nociceptive pain, cancer pain,neuropathic pain and psychogenic pain syndrome.

Examples of substance use disorders which may be treated using thecompounds and compositions of the invention include but are not limitedto drug addiction, drug abuse, drug habituation, drug dependence,withdrawal syndrome and overdose.

Examples of cancers which may be treated using the compounds andcompositions of the invention include but are not limited to glioma,melanoma, gastrointestinal stromal tumor (GIST), small cell lung cancer,colorectal cancer, and other solid tumors.

Examples of cardiovascular diseases which may be treated using thecompounds and compositions of the invention include but are not limitedto angina pectoris, myocardial infarction, congestive heart failure,cardiomyopathy, hypertension, arterial stenosis, and venous stenosis.

More particularly, the compounds of the invention may be used for thetreatment and prevention of asthma, atopic dermatitis, urticaria,irritable bowel syndrome (IBS), or a fibrotic disease including but notlimited to scleroderma, pulmonary fibrosis, idiopathic pulmonaryfibrosis (IPF), primary pulmonary hypertension (PPH), primary pulmonaryarterial hypertension (PPAH), idiopathic arterial hypertension (IPAH),liver fibrosis, renal fibrosis and cardiac fibrosis.

Furthermore, the present invention provides for the use of a compoundhaving Formula (1), (2A) or (2B), or a pharmaceutically compositionthereof, and optionally in combination with a second therapeutic agent,for the manufacture of a medicament for treating a disease or conditionmodulated by c-kit, PDGFRα, PDGFRβ, CSF1R, Abl, BCR-Abl, CSK, JNK1,JNK2, p38, p70S6K, TGFβ, SRC, EGFR, trkB, FGFR3, Fes, Lck, Syk, RAF,MKK4, MKK6, SAPK2β, BRK, Fms, KDR, c-raf or b-raf kinases; and moreparticularly, for the manufacture of a medicament for treating a diseaseor condition modulated by PDGFRα, PDGFRβ or c-kit.

In the above methods for using the compounds of the invention, acompound having Formula (1), (2A) or (2B) may be administered to asystem comprising cells or tissues. In other embodiments, a compoundhaving Formula (1), (2A) or (2B) may be administered to a human oranimal subject.

Definitions

“Alkyl” refers to a moiety and as a structural element of other groups,for example halo-substituted-alkyl and alkoxy, and may bestraight-chained or branched. An optionally substituted alkyl, alkenylor alkynyl as used herein may be optionally halogenated (e.g., CF₃), ormay have one or more carbons that is substituted or replaced with aheteroatom, such as NR, O or S (e.g., —OCH₂CH₂O—, alkylthiols,thioalkoxy, alkylamines, etc).

“Aryl” refers to a monocyclic or fused bicyclic aromatic ring containingcarbon atoms. For example, aryl may be phenyl or naphthyl. “Arylene”means a divalent radical derived from an aryl group.

“Heteroaryl” as used herein is as defined for aryl above, where one ormore of the ring members is a heteroatom. Examples of heteroarylsinclude but are not limited to pyridyl, indolyl, indazolyl,quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl,benzo[1,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl,oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.

A “carbocyclic ring” as used herein refers to a saturated or partiallyunsaturated, monocyclic, fused bicyclic or bridged polycyclic ringcontaining carbon atoms, which may optionally be substituted, forexample, with ═O. Examples of carbocyclic rings include but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylene, cyclohexanone, etc.

A “heterocyclic ring” as used herein is as defined for a carbocyclicring above, wherein one or more ring carbons is a heteroatom. Forexample, a heterocyclic ring may contain N, O, S, —N═, —S—, —S(O),—S(O)₂—, or —NR— wherein R may be hydrogen, C₁₋₄alkyl or a protectinggroup. Examples of heterocyclic rings include but are not limited tomorpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl,piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.

As used herein, an H atom in any substituent groups (e.g., CH₂)encompasses all suitable isotopic variations, e.g., H, ²H and ³H.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted,” it is meant that the substituent is a groupthat may be substituted with one or more group(s) individually andindependently selected from, for example, an optionally halogenatedalkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, alkynyl, amide,amino, including mono- and di-substituted amino groups, aryl, aryloxy,arylthio, carbonyl, carbocyclic, cyano, cycloalkyl, halogen,heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclic,hydroxy, isocyanato, isothiocyanato, mercapto, nitro, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, perhaloalkyl,perfluoroalkyl, silyl, sulfonyl, thiocarbonyl, thiocyanato,trihalomethanesulfonyl, and the protected compounds thereof. Theprotecting groups that may form the protected compounds of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts, Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, andKocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, whichare incorporated herein by reference in their entirety.

The terms “co-administration” or “combined administration” or the likeas used herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein refers to a productobtained from mixing or combining active ingredients, and includes bothfixed and non-fixed combinations of the active ingredients. The term“fixed combination” means that the active ingredients, e.g. a compoundof Formula (1) and a co-agent, are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the active ingredients, e.g. acompound of Formula (1) and a co-agent, are both administered to apatient as separate entities either simultaneously, concurrently orsequentially with no specific time limits, wherein such administrationprovides therapeutically effective levels of the active ingredients inthe body of the patient. The latter also applies to cocktail therapy,e.g. the administration of three or more active ingredients.

The term “therapeutically effective amount” means the amount of thesubject compound that will elicit a biological or medical response in acell, tissue, organ, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician.

The term “administration” or “administering” of the subject compoundmeans providing a compound of the invention and prodrugs thereof to asubject in need of treatment.

Unless otherwise stated for this invention, a kinase selected fromc-kit, PDGFRα, PDGFRβ, CSF1R, Abl, BCR-Abl, CSK, JNK1, JNK2, p38,p70S6K, TGFβ, SRC, EGFR, trkB, FGFR3, Fes, Lck, Syk, RAF, MKK4, MKK6,SAPK2β, BRK, Fms, KDR, c-raf and b-raf refers to wild-type and mutantforms (i.e., having single or multiple amino acid changes from thewild-type sequence).

MODES OF CARRYING OUT THE INVENTION

The present invention provides compounds and pharmaceutical compositionsthereof, which may be useful as protein kinase inhibitors.

In one aspect, the present invention provides compounds of Formula (1):

-   -   or a pharmaceutically acceptable salt thereof;    -   R¹ is a haloalkyl having 1-6 fluorine atoms;    -   R² is C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which        may be optionally substituted with halo, amino or hydroxyl        groups; halo, cyano, nitro, (CR₂)_(k)OR⁷, (CR₂)_(k)O(CR₂)₁₋₄R⁷,        (CR₂)_(k)SR⁷, (CR₂)_(k)NR⁹R¹⁰, (CR₂)_(k)C(O)O₀₋₁R⁷, OC(O)R⁷,        (CR₂)_(k)C(S)R⁷, (CR₂)_(k)C(O)NR⁹R¹⁰,        (CR₂)_(k)C(O)NR(CR₂)₀₋₆C(O)O₀₋₁R⁷, (CR₂)_(k)NRC(O)O₀₋₁R⁷,        (CR₂)_(k)S(O)₁₋₂NR⁹R¹⁰, (CR₂)_(k)S(O)₁₋₂R⁸, (CR²)_(k)NRS(O)₁₋₂R⁸        or (CR₂)_(k)R⁶; or any two adjacent R² groups together may form        an optionally substituted 5-8 membered carbocyclic,        heterocyclic, aryl or heteroaryl ring;    -   R³ is -L-NR⁴R⁵, —X—NR—C(O)R⁸ or —X—NR—C(O)NR⁴R⁵ wherein L is        —X—C(O), —X—OC(O), —(CR₂)_(j), —SO₀₋₂(CR₂)_(j), —O(CR₂)₁₋₄, or

-   -    and X is (CR₂)_(j) or [C(R)(CR₂OR)];    -   R⁴, R⁵, R⁹ and R¹⁰ are independently H; C₁₋₆ alkyl, C₂₋₆ alkenyl        or C₂₋₆ alkynyl, each of which may be optionally substituted        with halo, amino, hydroxyl, alkoxy, cyano, carboxyl or R⁶;        (CR₂)_(k)CN, (CR₂)₁₋₆NR⁷R⁷, (CR₂)₁₋₆OR⁷, (CR₂)_(k)C(O)O₀₋₁R⁷,        (CR₂)_(k)C(O)NR⁷R⁷ or (CR₂)_(k)—R⁶;    -   R⁶ is an optionally substituted C₃₋₇ cycloalkyl, C₆ aryl, or a        5-6 membered heteroaryl or 5-7 membered heterocyclic ring;    -   R⁷ and R⁸ are independently (CR₂)_(k)—R⁶ or C₁₋₆ alkyl, C₂₋₆        alkenyl or C₂₋₆ alkynyl, each of which may be optionally        substituted with halo, amino, amido, hydroxyl, alkoxy, cyano,        carboxyl or R⁶; or R⁷ is H;    -   alternatively, R⁴ and R⁵ together with N in each NR⁴R⁵, R⁷ and        R⁷ together with N in NR⁷R⁷ or R⁹ and R¹⁰ together with N in        NR⁹R¹⁰ may form a 4-7 membered heterocyclic ring optionally        substituted with 1-3 R¹¹ groups;    -   R¹¹ is R⁸, (CR₂)_(k)—OR⁷, CO₂R⁷, (CR₂)_(k)—C(O)—(CR₂)_(k)—R⁸,        (CR₂)_(k)C(O)NR⁷R⁷, (CR₂)_(k)C(O)NR(CR₂)₀₋₆C(O)O₀₋₁R⁷,        (CR₂)_(k)NRC(O)O₀₋₁R⁷, (CR₂)_(k)S(O)₁₋₂NR⁷R⁷, (CR₂)_(k)S(O)₁₋₂R⁸        or (CR₂)_(k)NRS(O)₁₋₂R⁸;    -   each R is H or C₁₋₆alkyl;    -   each k is 0-6; and    -   j and m are independently 0-4;    -   provided R¹ is not trifluoromethoxy when R³ is C(O)NH₂,        C(O)NR¹²R¹³ or SO₂NH(CH₂)₂₋₃NR¹⁴R¹⁵; wherein R¹² and R¹³        together form piperazinyl and R¹⁴ and R¹⁵ together form        morpholinyl.

In one embodiment, the compounds have Formula (2A) or (2B):

-   -   wherein R⁴ and R⁵ together with N form a 5-6 membered        heterocyclic ring optionally containing NR¹⁶, O, S, ═O or a        double bond; wherein said heterocyclic ring is optionally        substituted with 1-2 R¹¹ groups;    -   R¹⁶ is H, R⁸, —(CR₂)₁₋₄CO₂R⁷, (CR₂)_(k)—C(O)—(CR₂)_(k)—R⁸,        (CR₂)_(k)C(O)NR⁷R⁷, (CR₂)_(k)C(O)NR(CR₂)₀₋₆C(O)O₀₋₁R⁷,        (CR₂)₁₋₄NRC(O)O₀₋₁R⁷, (CR₂)_(k)S(O)₁₋₂NR⁷R⁷, (CR₂)_(k)S(O)₁₋₂R⁸        or (CR₂)_(k)NRS(O)₁₋₂R⁸; and    -   R⁴, R⁵, R⁷, R⁸, R¹¹, R and k are as defined in Formula (1).

In each of the above formula, any asymmetric carbon atoms may be presentin the (R)-, (S)- or (R,S)-configuration. The compounds may thus bepresent as mixtures of isomers or as pure isomers, for example, as pureenantiomers or diastereomers. The invention further encompasses possibletautomers of the inventive compounds.

The present invention also includes all suitable isotopic variations ofthe compounds of the invention, or pharmaceutically acceptable saltsthereof. An isotopic variation of a compound of the invention or apharmaceutically acceptable salt thereof is defined as one in which atleast one atom is replaced by an atom having the same atomic number butan atomic mass different from the atomic mass usually found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention and pharmaceutically acceptable salts thereof include but arenot limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cl and ¹²³I. Certainisotopic variations of the compounds of the invention andpharmaceutically acceptable salts thereof, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies.

In particular examples, ²H, ³H and ¹⁴C isotopes may be used for theirease of preparation and detectability. In other examples, substitutionwith isotopes such as ²H may afford certain therapeutic advantagesresulting from greater metabolic stability, such as increased in vivohalf-life or reduced dosage requirements. Isotopic variations of thecompounds of the invention or pharmaceutically acceptable salts thereofcan generally be prepared by conventional procedures using appropriateisotopic variations of suitable reagents. Isotopic variations of thecompounds have the potential to change a compound's metabolic fateand/or create small changes in physical properties such ashydrophobicity, and the like. Isotopic variation have the potential toenhance efficacy and safety, enhance bioavailability and half-life,alter protein binding, change biodistribution, increase the proportionof active metabolites and/or decrease the formation of reactive or toxicmetabolites.

In each of the above formula, each optionally substituted moiety may besubstituted with C₁₋₆ alkyl, C₂₋₆ alkenyl or C₃₋₆ alkynyl, each of whichmay be optionally halogenated or optionally having a carbon that may bereplaced or substituted with N, S, O, or a combination thereof (forexample, hydroxylC₁-C₈alkyl, C₁-C₈alkoxyC₁-C₈alkyl); halo, amino,amidino, C₁₋₆ alkoxy; hydroxyl, methylenedioxy, carboxy; C₁₋₈alkylcarbonyl, C₁₋₈ alkoxycarbonyl, carbamoyl, C₁₋₈ alkylcarbamoyl,sulfamoyl, cyano, oxo, nitro, or an optionally substituted carbocyclicring, heterocyclic ring, aryl or heteroaryl as previously described.

Compounds having Formula (1), (2A) or (2B) in free form or inpharmaceutically acceptable salt form, may exhibit valuablepharmacological properties, for example, as indicated by the in vitrotests described in this application. The IC₅₀ value in those experimentsis given as that concentration of the test compound in question thatresults in a cell count that is 50% lower than that obtained using thecontrol without inhibitor. In general, compounds of the invention haveIC₅₀ values from 1 nM to 10 μM. In some examples, compounds of theinvention have IC₅₀ values from 0.01 μM to 5 μM. In other examples,compounds of the invention have IC₅₀ values from 0.01 μM to 1 μM, ormore particularly from 1 nM to 1 μM. In yet other examples, compounds ofthe invention have IC₅₀ values of less than 1 nM or more than 10 μM.Formula (1), (2A) and (2B) may exhibit a percentage inhibition ofgreater than 50%, or in other embodiments, may exhibit a percentageinhibition greater than about 70%, against one or more of the followingkinases at 10 μM: c-kit, PDGFRα, PDGFRβ, CSF1R, Abl, BCR-Abl, CSK, JNK1,JNK2, p38, p70S6K, TGFβ, SRC, EGFR, trkB, FGFR3, Fes, Lck, Syk, RAF,MKK4, MKK6, SAPK2β, BRK, Fms, KDR, c-raf or b-raf kinases.

The compounds of the invention may also be used for the treatment of akinase-mediated condition or disease, such as diseases mediated byc-kit, PDGFRα, PDGFRβ, CSF1R, Abl, BCR-Abl, CSK, JNK1, JNK2, p38,p70S6K, TGFβ, SRC, EGFR, trkB, FGFR3, Fes, Lck, Syk, RAF, MKK4, MKK6,SAPK2β, BRK, Fms, KDR, c-raf or b-raf kinases.

More particularly, the compounds of the invention may be used for thetreatment and prevention of asthma, atopic dermatitis, urticaria,irritable bowel syndrome (IBS), or a fibrotic disease including but notlimited to scleroderma, pulmonary fibrosis, idiopathic pulmonaryfibrosis (IPF), primary pulmonary hypertension (PPH), primary pulmonaryarterial hypertension (PPAH), idiopathic arterial hypertension (IPAH),liver fibrosis, renal fibrosis and cardiac fibrosis.

Pharmacology and Utility

Compounds of the invention are screened against the kinase panel (wildtype and/or mutation thereof) and may modulate the activity of at leastone panel kinase panel member. As such, compounds of the invention maybe useful for treating diseases or disorders in which kinases contributeto the pathology and/or symptomology of the disease. Examples of kinasesthat may be inhibited by the compounds and compositions described hereinand against which the methods described herein may be useful include,but are not limited to c-kit, PDGFRα, PDGFRβ, CSF1R, Abl, BCR-Abl, CSK,JNK1, JNK2, p38, p70S6K, TGFβ, SRC, EGFR, trkB, FGFR3, Fes, Lck, Syk,RAF, MKK4, MKK6, SAPK2β, BRK, Fms, KDR, c-raf or b-raf kinases.

c-Kit

Mast cells are tissue elements derived from a particular subset ofhematopoietic stem cells that express CD34, c-kit and CD13 antigens.Mast cells are characterized by their heterogeneity, not only regardingtissue location and structure but also at the functional andhistochemical levels. Immature mast cell progenitors circulate in thebloodstream and differentiate into various tissues. Thesedifferentiation and proliferation processes are under the influence ofcytokines, one of importance being Stem Cell Factor (SCF), also termedthe Kit ligand, Steel factor or Mast Cell Growth Factor. The Stem CellFactor receptor is encoded by the protooncogene, c-kit, which isexpressed in hematopoietic progenitor cells, mast cells, germ cells,interstitial cells of Cajal (ICC), and some human tumors, and is alsoexpressed by non hematopoietic cells.

Tyrosine kinases are receptor type or non-receptor type proteins, whichtransfer the terminal phosphate of ATP to tyrosine residues of proteinsthereby activating or inactivating signal transduction pathways. TheStem Cell Factor receptor, c-kit, is a Type III transmembrane receptorprotein tyrosine kinase which initiates cell growth and proliferationsignal transduction cascades in response to SCF binding. Ligation ofc-kit receptor by SCF induces its dimerization followed by itstransphorylation, leading to the recruitment and activation of variousintracytoplasmic substrates. These activated substrates induce multipleintracellular signaling pathways responsible for cell proliferation andactivation. These proteins are known to be involved in many cellularmechanisms, which in case of disruption, lead to disorders such asabnormal cell proliferation and migration, as well as inflammation. Thecompounds of the present invention may inhibit cellular processesinvolving SCF, such as inhibiting SCF receptor autophosphorylation andSCF-stimulated activation of MAPK kinase (mitogen-activated proteinkinase).

The activity of the c-kit receptor protein tyrosine kinase is regulatedin normal cells, and the normal functional activity of the c-kit geneproduct is important for the maintenance of normal hematopoeisis,melanogenesis, gametogenesis, and growth and differentiation of mastcells. In addition to its importance in normal cellular physiologicactivities, c-kit plays a role in the biological aspects of certainhuman cancers, and unregulated c-kit kinase activity is implicated inthe pathogenesis of human cancers, and in certain tumors types.Proliferation of tumor cell growth mediated by c-kit can occur by aspecific mutation of the c-kit polypeptide that results in ligandindependent activation or by autocrine stimulation of the receptor. Inthe former case, mutations that cause constitutive activation of c-kitkinase activity in the absence of SCF binding are implicated inmalignant human cancers, including germ cell tumors, mast cell tumors,gastrointestinal stromal tumors, small-cell lung cancer, melanoma,breast cancer, acute myelogenous leukemia, neuroblastoma andmastocytosis.

Mast cells present in tissues of patients are implicated in orcontribute to the genesis of diseases such as autoimmune diseases(multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases(IBD)), allergic diseases, tumor angiogenesis, inflammatory diseases,and interstitial cystitis. Allergic diseases include but are not limitedto allergic rhinitis, allergic sinusitis, anaphylactic syndrome,urticaria, angioedema, atopic dermatitis, allergic contact dermatitis,erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis,insect bite skin inflammation, and asthma. Asthma is characterized byairflow obstruction, bronchial hyper responsiveness and airwayinflammation, and includes bronchial asthma and allergic asthma.

In these diseases, mast cells participate in the destruction of tissuesby releasing a cocktail of different proteases and mediators such ashistamine, neutral proteases, lipid-derived mediators (prostaglandins,thromboxanes and leucotrienes), and various cytokines (IL-1, IL-2, IL-3,IL-4, IL-5, IL-6, IL-8, TNF-A, GM-CSF, MIP-LA, MIP-1b, MIP-2 and IFN-y).Mast cell activation induces diverse effector responses, such assecretion of allergic mediators, proteases, chemokines such as MCP-1 andRANTES, leukotrienes, prostaglandins, neurotrophins, induction ofcytokine gene transcription (IL-4, IL-5, IL-6, IL-13, TNFA and GM-CSF).These mediators contribute to creating the asthmatic phenotype by theireffects on endothelial cells, smooth muscle cells and fibroblasts and onextracellular matrix, and by recruiting other inflammatory cells.

Mast cells may play a role in asthma as suggested by the humanizedanti-IgE monoclonal antibody treatment. The rationale of anti-IgEtherapy is to specifically target IgE with the result of inactivatingfree anti-IgE and halting further IgE production. In addition, since IgElevels are a major regulator of the level of expression of IgE receptorFceRI, one aim of this therapy is to decrease FceRI expression on mastcells and basophils, and, as a consequence, to decrease the capacity ofthese cells to be activated. The capacity of the anti-IgE therapy todecrease FceRI expression has been demonstrated on basophils. Thedecrease in FceRI expression on basophils is associated with a decreasein the capacity of basophils to secrete mediators upon activation.

C-kit inhibitors may also be used in the treatment ofnon-insulin-dependent diabetes mellitus (NLDDM), also known as type IIdiabetes, a chronic disease appearing when insulin is inefficient inpromoting glucose uptake by cells, resulting in increased levels ofglucose in the blood. This disease affects about 100 million peopleworld-wide, 75% of which are obese at the time of diagnosis. Over manyyears, the failure of the glucose uptake regulation leads to thedevelopment of Type II diabetes, and the blood glucose level needs to beregulated with medicinal products. Ultimately, unregulated blood glucoselevel is responsible for blood vessels, kidney and eye damages, as wellas cardiovascular diseases. This tissue damages contribute to mortalityin diabetics.

In addition, the activation of mast cells by different stimuli such asstress, trauma, infection as well as neurotransmitters, may participatein the exacerbation of the chemical imbalance causing CNS disorders.More specifically, mast cell degranulation is stimulated by commonneurotransmitters such as neurotensin, somatostatin, substance P andacetylcholine, by growth or survival factors, notably NGF, TGFβL Mastcells involved in the response to such stimulus can be brain mast cellsbut also other mast cells releasing the content of their granules in theblood stream that ultimately reach sensory, motor or brain neurons.Brain mast cells staining is CTMC staining-like but they show thesecretory pattern of MMC, implying that they constitute a particularsubset of mast cells presenting specificities.

Following mast cells activation, released granules liberate variousfactors capable of modulating and altering neurotransmission and neuronssurvival. Among such factors, serotonin is important since an increaseof the level of free serotonin has been observed in depressed patients.Alternatively, the sudden burst of serotonin may be followed by a periodof serotonin shortage, leading to pain and migraine. As a consequence,it is believed that mast cells exacerbate in autocrine or paracrinemanner the deregulation of neurotransmission. For example, anxiety orstress-induced release of neurotransmitters such as serotonin activatesmast cells, which in turn release the content of their granules, furthercontributing to the chemical imbalance in the brain leading to CNSdisorders.

Other mediators released by mast cells can be categorized intovasoactive, nociceptive, proinflammatory and other neurotransmitters.Taken together, these factors are able to induce great disturbance inthe activity of neurons, whether they are sensory, motor, or CNSneurons. In addition, patients afflicted with mastocytosis are moreinclined to develop CNS disorders than the normal population. This canbe explained by the presence of activating mutations in the c-kitreceptor, which induce degranulation of mast cells and a burst offactors contributing to chemical imbalance and neurotransmissionalteration.

In some cases, activated mast cells can also participate in thedestruction of neuronal tissues by releasing a cocktail of differentproteases and mediators categorized into three groups: preformedgranule-associated mediators (histamine, proteoglycans, and neutralproteases), lipid-derived mediators (prostaglandins, thromboxanes andleucotrienes), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5,IL-6, IL-8, TNF-A, GM-CSF, MIP-LA, MIP-1b, MIP-2 and IFN-y). Theliberation by activated mast cells of mediators (TNF-A, histamine,leukotrienes, prostaglandins etc.) as well as proteases may i) induceinflammation and vasodilatation and ii) participate in the neuronaltissue destruction process Inhibition of c-kit activity reduces cellularproliferation, depleting the mast cells responsible for diseases and/orconditions, thereby suggesting a role for use of inhibitors of c-kit inthe treatment of c-kit dependent diseases and/or conditions, such as CNSdisorders.

Mast cells have also been identified to be involved in or to contributeto drug dependence and withdrawal symptoms. Drug dependence is theresult of a phenomenon called tolerance, which is the need to increasethe dose of the drug to maintain its full effect, and of physicaldependence, which is the habituation of the body to a drug. When theintake of a drug is discontinued, individual may experience unpleasantwithdrawal syndrome.

The activation of mast cells by different drugs, including, but notlimited to, salicylic derivatives, morphine derivatives, opioids,heroin, amphetamines, alcohol, nicotine, analgesics, anesthetics, andanxyolitics results in the degranulation of mast cells, whichparticipate in the exacerbation of the chemical imbalance responsiblefor drug habituation and withdrawal syndrome. Following mast cellsactivation, released granules liberate various factors capable ofmodulating and altering neurotransmission. Among such factors ismorphine which is bound or stored in mast cells granules. Tobacco smokealso induces the release of mediators from canine mast cells andmodulates prostaglandin production leading to asthma. In addition,patients afflicted with mastocytosis are more incline to developsubstance use disorders than the normal population. This can beexplained by the presence of activating mutations in the c-kit receptor,which induce degranulation of mast cells and a burst of factorscontributing to chemical imbalance and neurotransmission alteration.

Presently, there is no available treatment that provides relief and helpfor individuals to withdraw from substance abuse disorders. C-kitinhibitors may be used for treating substance abuse disorders,particularly drug addiction, drug abuse, drug habituation, drugdependence, withdrawal syndrome and overdose, comprising administering acompound capable of depleting mast cells to a human in need of suchtreatment.

c-Kit has a substantial homology to the PDGF receptor and to the CSF-1receptor (c-Fms). Investigations on various erythroid and myeloid celllines indicate an expression of the c-Kit gene in early stages ofdifferentiation (Andre et al., Oncogene 4 (1989), 1047-1049). Certaintumors such as glioblastoma cells likewise exhibit a pronouncedexpression of the c-Kit gene.

PDGF (Platelet-Derived Growth Factor)

PDGF (Platelet-derived Growth Factor) plays an important role both innormal growth and also in pathological cell proliferation. Compounds ofthe invention may inhibit PDGF receptor (PDGFR) activity, and may beused as an agent to treat non-malignant proliferative disorders, such asscleroderma and other fibrotic disorders, atherosclerosis, thrombosis orpsoriasis. The compounds of the present invention may also be used as atumor-inhibiting substance, for example in small cell lung cancer,gliomas, sarcomas, prostate tumors, and tumors of the colon, breast, andovary.

In one embodiment, the compounds of the invention may be used for thetreatment and prevention of a fibrotic disorder or disease, a conditionlinked to or associated with the formation and deposition ofextracellular matrix components in the internal organs, including thekidneys, heart, lungs, liver, skin and joints. Various studies haveimplicated PDGFR as a central player in fibrotic responses to tissueinjury, e.g.:

-   -   i) PDGF is upregulated in alveolar macrophages from patients        with idiopathic pulmonary fibrosis (IPF);    -   ii) PDGFRβ is one of the first genes upregulated after        activation of hepatic stellate cells to become myofibroblasts, a        central step in development of fibrosis in the liver;    -   iii) PDGF and its receptors are significantly upregulated in        scleroderma, and similarly upregulated in the process of renal        fibrogenesis;    -   iv) PDGF is induced by injury and/or pro-inflammatory cytokines,        or in an autocrine fashion on myofibroblasts driving their        proliferation, differentiation, and migration. These        myofibroblasts then secrete extracellular matrix proteins and        collagen leading to scarring and progressive organ damage. TGFβ        secretion also contributes significantly to the production of        collagen during fibrogenesis;    -   v) A PDGF-C transgene induces the development of liver fibrosis        in mice, while a soluble dominant-negative version of PDGFRβ        prevents liver fibrosis in ratsl; and    -   vi) Administration of PDGF-B to the kidney promoted signs of        renal fibrogenesis in rats.

Fibrotic disorders or diseases which may be treated using the compoundsof the invention include fibrotic lung diseases such as pulmonaryfibrosis (or interstitial lung disease or interstitial pulmonaryfibrosis), idiopathic pulmonary fibrosis, primary pulmonaryhypertension, idiopathic pulmonary arterial hypertension, the fibroticelement of pneumoconiosis (which is associated with exposure toenvironmental hazards such as smoking, asbestos, cotton lint, stonedust, mine dust and other particles), pulmonary sarcoidosis, fibrosingalveolitis, the fibrotic or hypertrophic element of cystic fibrosis,chronic obstructive pulmonary disease, adult respiratory distresssyndrome and emphysema. The compounds of the invention may also be usedfor the treatment and prevention of diseases that have as amanifestation fibrotic hypertrophy of the kidneys (renal fibrosis),liver (liver fibrosis), heart (cardiac fibrosis), prostate (e.g., benignprostatic hypertrophy (BPH)), pleura (e.g., pleurisy, pleural fibrosis),pancreas, and of the skin and/or muscle tissues such as scleroderma,eosinophilic fasciitis, discoid lesions associated with lupus or discoidlupus or surgical adhesions.

Other fibrotic disorders or diseases which may be treated using thecompounds of the invention include but are not limited to systemicsclerosis, mixed connective tissue disease, fibrodysplasia, fibrocysticdisease, sarcoidosis, myositis (e.g. polymyositis, primary idiopathicpolymyositis, childhood polymyositis, dermatomyositis, childhooddermatomyositis, primary idiopathic dermatomyositis in adults, inclusionbody myositis, polymyositis or dermatomyositis associated with malignanttumors); diseases that have as a manifestation fibrotic vascular intimalhypertrophy, such as vasculitis (including coronary artery vasculitis),polyarteritis nodosa or temporal arteritis; diseases that have as amanifestation fibrotic hypertrophy of nerve tissue such ascerebrosclerosis, annular sclerosis. diffuse sclerosis and lobarsclerosis; and diseases that have as a manifestation fibrotichypertrophy or fibrosis of the bowel wall, such as inflammatory boweldisease, including Crohn's disease.

Furthermore, the compounds of the present invention may also be usefulfor the protection of stem cells, for example to combat the hemotoxiceffect of chemotherapeutic agents, such as 5-fluorouracil; and may alsobe useful for the treatment of asthma and hypereosinophilia. Compoundsof the invention may especially be used for the treatment of diseaseswhich respond to an inhibition of the PDGF receptor kinase.

Compounds of the present invention may also exhibit useful effects inthe treatment of disorders arising as a result of transplantation, forexample, allogenic transplantation, especially tissue rejection, such asobliterative bronchiolitis (OB), i.e. a chronic rejection of allogeniclung transplants. In contrast to patients without OB, those with OBoften show an elevated PDGF concentration in bronchoalveolar lavagefluids.

Compounds of the present invention may also be effective againstdiseases associated with vascular smooth-muscle cell migration andproliferation (where PDGF and PDGFR often also play a role), such asrestenosis and atherosclerosis. These effects and the consequencesthereof for the proliferation or migration of vascular smooth-musclecells in vitro and in vivo may be demonstrated by administration of thecompounds of the present invention, and also by investigating its effecton the thickening of the vascular intima following mechanical injury invivo.

CSF1R (FMS)

The protein encoded by this gene is the receptor for colony stimulatingfactor 1, a cytokine which controls the production, differentiation, andfunction of macrophages. CSFR1 mediates most if not all of thebiological effects of this cytokine. The encoded protein is a tyrosinekinase transmembrane receptor and member of the CSF1/PDGF receptorfamily of tyrosine-protein kinases. Mutations in this gene have beenassociated with a predisposition to myeloid malignancy. (See e.g., Casaset al., Leuk. Lymphoma 2003 44:1935-41).

Abl, Trk, Syk, Ras, Raf, MAPK, TGFβ, FGFR3, c-Src, SAPK, Lck, Fes, Csk

Abelson tyrosine kinase (i.e. Abl, c-Abl) is involved in the regulationof the cell cycle, in the cellular response to genotoxic stress, and inthe transmission of information about the cellular environment throughintegrin signaling. The Abl protein appears to serve a complex role as acellular module that integrates signals from various extracellular andintracellular sources and that influences decisions in regard to cellcycle and apoptosis. Abelson tyrosine kinase includes sub-typesderivatives such as the chimeric fusion (oncoprotein) BCR-Abl withderegulated tyrosine kinase activity or the v-Abl.

The fusion protein BCR-Abl is a result of a reciprocal translocationthat fuses the Abl proto-oncogene with the Bcr gene. BCR-Abl is thencapable of transforming B-cells through the increase of mitogenicactivity. This increase results in a reduction of sensitivity toapoptosis, as well as altering the adhesion and homing of CML progenitorcells.

BCR-Abl is important in the pathogenesis of 95% of chronic myelogenousleukemia (CML) and 10% of acute lymphocytic leukemia. STI-571 (GLEEVEC®)is an inhibitor of the oncogenic BCR-Abl tyrosine kinase and is used forthe treatment of chronic myeloid leukemia (CML). However, some patientsin the blast crisis stage of CML are resistant to STI-571 due tomutations in the BCR-Abl kinase. Over 22 mutations have been reported todate, such as G250E, E255V, T315I, F317L and M351T.

Compounds of the present invention may inhibit abl kinase, for example,v-abl kinase. The compounds of the present invention may also inhibitwild-type BCR-Abl kinase and mutations of BCR-Abl kinase, and thus maybe suitable for the treatment of Bcr-abl-positive cancer and tumordiseases, such as leukemias (especially chronic myeloid leukemia andacute lymphoblastic leukemia, where especially apoptotic mechanisms ofaction are found). Compounds of the present invention may also beeffective against leukemic stem cells, and may be potentially useful forthe purification of these cells in vitro after removal of said cells(for example, bone marrow removal), and reimplantation of the cells oncethey have been cleared of cancer cells (for example, reimplantation ofpurified bone marrow cells).

The trk family of neurotrophin receptors (trkA, trkB, trkC) promotes thesurvival, growth and differentiation of the neuronal and non-neuronaltissues. The TrkB protein is expressed in neuroendocrine-type cells inthe small intestine and colon, in the alpha cells of the pancreas, inthe monocytes and macrophages of the lymph nodes and of the spleen, andin the granular layers of the epidermis (Shibayama and Koizumi, 1996).Expression of the TrkB protein has been associated with an unfavorableprogression of Wilms tumors and of neuroblastomas. Moreover, TrkB isexpressed in cancerous prostate cells but not in normal cells. Thesignaling pathway downstream of the trk receptors involves the cascadeof MAPK activation through the Shc, activated Ras, ERK-1 and ERK-2genes, and the PLC-gammal transduction pathway (Sugimoto et al., 2001).

Syk is a tyrosine kinase that plays an important role in mast celldegranulation and eosinophil activation. Accordingly, Syk kinase isimplicated in various allergic disorders, particularly asthma. It hasbeen shown that Syk binds to the phosphorylated gamma chain of the FceR1receptor via N-terminal SH2 domains and is important for downstreamsignaling.

The Ras-Raf-MEK-ERK signaling pathway mediates cellular response togrowth signals. Ras is mutated to an oncogenic form in ˜15% of humancancer. The Raf family belongs to the serine/threonine protein kinaseand includes three members, A-Raf, B-Raf and c-Raf (or Raf-1). B-Raf mayhave a prominent role in the formation of certain tumors with norequirement for an activated Ras allele (Nature 417: 949-954 (2002)).B-Raf mutations have been detected in a large percentage of malignantmelanomas.

Existing medical treatments for melanoma are limited in theireffectiveness, especially for late stage melanomas. The compounds of thepresent invention also inhibit cellular processes involving b-Rafkinase, providing a new therapeutic opportunity for treatment of humancancers, especially for melanoma.

Mitogen-activated protein kinases (MAPKs) are members of conservedsignal transduction pathways that activate transcription factors,translation factors and other target molecules in response to a varietyof extracellular signals. MAPKs are activated by phosphorylation at adual phosphorylation motif having the sequence Thr-X-Tyr bymitogen-activated protein kinase kinases (MKKs). In higher eukaryotes,the physiological role of MAPK signaling has been correlated withcellular events such as proliferation, oncogenesis, development anddifferentiation. Accordingly, the ability to regulate signaltransduction via these pathways (particularly via MKK4 and MKK6) couldlead to the development of treatments and preventive therapies for humandiseases associated with MAPK signaling, such as inflammatory diseases,autoimmune diseases and cancer.

Multiple forms of p38 MAPK (α, β, γ, δ), each encoded by a separategene, form part of a kinase cascade involved in the response of cells toa variety of stimuli, including osmotic stress, UV light and cytokinemediated events. These four isoforms of p38 are thought to regulatedifferent aspects of intracellular signaling. Its activation is part ofa cascade of signaling events that lead to the synthesis and productionof pro-inflammatory cytokines like TNFα. P38 functions byphosphorylating downstream substrates that include other kinases andtranscription factors. Agents that inhibit p38 kinase have been shown toblock the production of cytokines including but not limited to TNFα,IL-6, IL-8 and IL-1β.

Peripheral blood monocytes (PBMCs) have been shown to express andsecrete pro-inflammatory cytokines when stimulated withlipopolysaccharide (LPS) in vitro. P38 inhibitors efficiently block thiseffect when PBMCs are pretreated with such compounds prior tostimulation with LPS. P38 inhibitors are efficacious in animal models ofinflammatory disease. The destructive effects of many disease states arecaused by the over production of pro-inflammatory cytokines. The abilityof p38 inhibitors to regulate this overproduction makes them useful asdisease modifying agents.

Molecules that block p38 function have been shown to be effective ininhibiting bone resorption, inflammation, and other immune andinflammation-based pathologies. Thus, a safe and effective p38 inhibitorwould provide a means to treat debilitating diseases that can beregulated by modulation of p38 signaling. Therefore, compounds of theinvention that inhibit p38 activity are useful for the treatment ofinflammation, osteoarthritis, rheumatoid arthritis, cancer, autoimmunediseases, and for the treatment of other cytokine mediated diseases.

Transforming growth factor-beta (TGFβ) denotes a superfamily of proteinsthat includes, for example, TGFβ1, TGFβ2, and TGFβ3, which arepleotropic modulators of cell growth and differentiation, embryonic andbone development, extracellular matrix formation, hematopoiesis, immuneand inflammatory responses. The members of the TGFβ family initiateintracellular signaling pathways leading ultimately to the expression ofgenes that regulate the cell cycle, control proliferative responses, orrelate to extracellular matrix proteins that mediate outside-in cellsignaling, cell adhesion, migration and intercellular communication.

Consequently, compounds of the invention that are inhibitors of the TGFβintracellular signaling pathway are useful therapeutics forfibroproliferative diseases, including kidney disorders associated withunregulated TGFβ activity and excessive fibrosis includingglomerulonephritis (GN), such as mesangial proliferative GN, immune GN,and crescentic GN. Other renal conditions include diabetic nephropathy,renal interstitial fibrosis, renal fibrosis in transplant patientsreceiving cyclosporin, and HIV-associated nephropathy. Collagen vasculardisorders include progressive systemic sclerosis, polymyositis,scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or thoseassociated with the occurrence of Raynaud's syndrome. Lung fibrosesresulting from excessive TGFβ activity include adult respiratorydistress syndrome, COPD, idiopathic pulmonary fibrosis, and interstitialpulmonary fibrosis often associated with autoimmune disorders, such assystemic lupus erythematosus and scleroderma, chemical contact, orallergies. Another autoimmune disorder associated withfibroproliferative characteristics is rheumatoid arthritis.Fibroproliferative conditions can be associated with surgical eyeprocedures. Such procedures include retinal reattachment surgeryaccompanying proliferative vitreoretinopathy, cataract extraction withintraocular lens implantation, and post glaucoma drainage surgery.

Fibroblast growth factor receptor 3 was shown to exert a negativeregulatory effect on bone growth and an inhibition of chondrocyteproliferation. Thanatophoric dysplasia is caused by different mutationsin fibroblast growth factor receptor 3. One mutation, TDII FGFR3, has aconstitutive tyrosine kinase activity which activates the transcriptionfactor Stat1, leading to expression of a cell-cycle inhibitor, growtharrest and abnormal bone development (Su et al., Nature, 1997, 386,288-292). FGFR3 is also often expressed in multiple myeloma-typecancers.

The kinase, c-Src, transmits oncogenic signals of many receptors. Forexample, over-expression of EGFR or HER2/neu in tumors leads to theconstitutive activation of c-src, which is characteristic for themalignant cell but absent from the normal cell. On the other hand, micedeficient in the expression of c-src exhibit an osteopetrotic phenotype,indicating a key participation of c-src in osteoclast function and apossible involvement in related disorders.

The family of human ribosomal S6 protein kinases consists of at least 8members (RSK1, RSK2, RSK3, RSK4, MSK1, MSK2, p70S6K and p70S6 Kb).Ribosomal protein S6 protein kinases play important pleotropicfunctions; among them is a key role in the regulation of mRNAtranslation during protein biosynthesis (Eur. J. Biochem 2000 November;267(21): 6321-30, Exp Cell Res. Nov. 25, 1999; 253 (1):100-9, Mol CellEndocrinol. May 25, 1999; 151(1-2):65-77). The phosphorylation of the S6ribosomal protein by p70S6 has also been implicated in the regulation ofcell motility (Immunol. Cell Biol. 2000 August; 78(4):447-51) and cellgrowth (Prog. Nucleic Acid Res. Mol. Biol., 2000; 65:101-27), and hence,may be important in tumor metastasis, the immune response and tissuerepair as well as other disease conditions.

The SAPK's (also called “jun N-terminal kinases” or “JNK's”) are afamily of protein kinases that represent the penultimate step in signaltransduction pathways that result in activation of the c-juntranscription factor and expression of genes regulated by c-jun. Inparticular, c-jun is involved in the transcription of genes that encodeproteins involved in the repair of DNA that is damaged due to genotoxicinsults. Agents that inhibit SAPK activity in a cell prevent DNA repairand sensitize the cell to those cancer therapeutic modalities that actby inducing DNA damage.

Lck plays a role in T-cell signaling. Mice that lack the Lck gene have apoor ability to develop thymocytes. The function of Lck as a positiveactivator of T-cell signaling suggests that Lck inhibitors may be usefulfor treating autoimmune disease such as rheumatoid arthritis.

Fes is strongly expressed in myeloid hematopoietic cells and isimplicated in both differentiation and survival signaling pathways inmyeloid leukocytes. CSK is implicated in cancers, particularlycolorectal and breast cancers.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount (See, “Administration and Pharmaceutical Compositions,” infra) ofa compound of Formula (1), (2A), (2B) or (C), or a pharmaceuticallyacceptable salt thereof. For any of the above uses, the required dosagewill vary depending on the mode of administration, the particularcondition to be treated and the effect desired.

Administration and Pharmaceutical Compositions

A pharmaceutical composition, as used herein, refers to a mixture of acompound of the invention with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism.Pharmaceutical compositions containing a compound of the invention maybe administered in therapeutically effective amounts as pharmaceuticalcompositions by any conventional form and route known in the artincluding, but not limited to: intravenous, oral, rectal, aerosol,parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal,and topical administration.

One may administer the compound in a local rather than systemic manner,for example, via injection of the compound directly into an organ, oftenin a depot or sustained release formulation. Furthermore, one mayadminister pharmaceutical composition containing a compound of theinvention in a targeted drug delivery system, for example, in a liposomecoated with organ-specific antibody. The liposomes will be targeted toand taken up selectively by the organ. In addition, pharmaceuticalcompositions containing a compound of the invention may be provided inthe form of a rapid release formulation, in the form of an extendedrelease formulation, or in the form of an intermediate releaseformulation.

For oral administration, a compound of the invention may be formulatedreadily by combining the active compounds with pharmaceuticallyacceptable carriers or excipients well known in the art. Such carriersenable the compounds described herein to be formulated as tablets,powders, pills, dragees, capsules, liquids, gels, syrups, elixirs,slurries, suspensions and the like, for oral ingestion by a patient tobe treated.

Pharmaceutical preparations for oral use may be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as: for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores may be provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which may be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, or gels formulated in conventional manner.Parental injections may involve bolus injection or continuous infusion.The pharmaceutical composition of a compound of the invention may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds of the invention may be administered topically and may beformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compounds may containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

Formulations suitable for transdermal administration may employtransdermal delivery devices and transdermal delivery patches, and maybe lipophilic emulsions or buffered, aqueous solutions, dissolved and/ordispersed in a polymer or an adhesive. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents. Still further, transdermal delivery of the compounds of theinvention may be accomplished by means of iontophoretic patches and thelike. Additionally, transdermal patches may provide controlled deliveryof the compounds of the invention. The rate of absorption may be slowedby using rate-controlling membranes or by trapping the compound within apolymer matrix or gel. Conversely, absorption enhancers may be used toincrease absorption. An absorption enhancer or carrier may includeabsorbable pharmaceutically acceptable solvents to assist passagethrough the skin. For example, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling bather todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

For administration by inhalation, the compounds of the invention may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsof the compounds of the invention may be conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridges,such as, by way of example only, gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds of the invention may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Pharmaceutical compositions may be formulated in conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which may be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. Pharmaceutical compositionscomprising a compound of the invention may be manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

The pharmaceutical compositions will include at least onepharmaceutically acceptable carrier, diluent or excipient and a compoundof Formula (1), (2A) or (2B) described herein as an active ingredient infree-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical compositions describedherein include the use of N-oxides, crystalline forms (also known aspolymorphs), as well as active metabolites of these compounds having thesame type of activity. In some situations, compounds may exist astautomers. All tautomers are included within the scope of the compoundspresented herein. Additionally, the compounds described herein may existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.In addition, the pharmaceutical compositions may include other medicinalor pharmaceutical agents, carriers, adjuvants, such as preserving,stabilizing, wetting or emulsifying agents, solution promoters, saltsfor regulating the osmotic pressure, and/or buffers. In addition, thepharmaceutical compositions may also contain other therapeuticallyvaluable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The compositions may be inliquid solutions or suspensions, solid forms suitable for solution orsuspension in a liquid prior to use, or as emulsions. These compositionsmay also contain minor amounts of nontoxic, auxiliary substances, suchas wetting or emulsifying agents, pH buffering agents, and so forth.

A summary of pharmaceutical compositions described herein may be found,for example, in Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999), herein incorporated by reference in their entirety.

Methods of Administration and Treatment Methods

The compositions containing the compound(s) described herein may beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. It is considered well within the skill of the art for one todetermine such therapeutically effective amounts by routineexperimentation (including, but not limited to, a dose escalationclinical trial).

The compounds of the invention may be used in combination with a secondtherapeutic agent. For example, if one of the side effects experiencedby a patient upon receiving one of the compounds herein is inflammation,the compounds of the invention may be administered with in combinationwith an anti-inflammatory agent. The therapeutic effectiveness of acompound described herein may also be enhanced by administration of anadjuvant. When the compounds of the invention are administered inconjunction with other therapies, dosages of the co-administeredcompounds will vary depending on the type of co-drug employed, on thespecific drug employed, on the disease or condition being treated and soforth. In addition, when co-administered with one or more biologicallyactive agents, the compounds of the invention may be administered eithersimultaneously with the biologically active agent(s), or sequentially.The administration of a compound of the invention in combination with asecond therapeutic agent may have an additive or synergistic effect.

In some examples, the compounds of the invention may be used incombination with an anti-fibrotic agent; e.g., an agent that interfereswith or modulates the progression of a fibrotic disease such asscleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF),primary pulmonary hypertension (PPH), primary pulmonary arterialhypertension (PPAH), idiopathic arterial hypertension (IPAH), liverfibrosis, renal fibrosis and cardiac fibrosis. Examples of anti-fibroticagents which may be used in combination with a compound of the inventioninclude but are not limited to pirfenidone (Nakazoto et al., Eur. J.Pharmacol. 446:177-185 (2002), tacrolimus (Nagano et al., Eur. Respir.J. 27: 460-469 (2006) or5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-methyl-1H-pyrrol-1-yl]prop-1-en-1-yl}-N-(methylsulfonyl)benzamide(SMP-534) (Sugaru et al., Am. J. Nephrology 26:50-58 (2006)). Thecompounds of the invention may also be used in combination with ananti-inflammatory agent, including, but not limited to, corticosteroidsand cromolyns, leukotriene antagonists, and IgE blockers such asomalizumab. In other examples, the compounds of the invention may beused in combination with a medication for treating asthma; e.g.,bronchodilators such as β₂-agonists, xanthines (e.g. methylxanthines)and anticholinerigcs; and an anti-inflammatory agent as described above.

The compounds of the invention may also be used in combination with achemotherapeutic agent to treat a cell proliferative disorder, includingbut not limited to, lymphoma, osteosarcoma, melanoma, or a tumor ofbreast, renal, prostate, colorectal, thyroid, ovarian, pancreatic,neuronal, lung, uterine or gastrointestinal tumor. Examples ofchemotherapeutic agents which may be used in the compositions andmethods of the invention include but are not limited to anthracyclines,alkylating agents (e.g., mitomycin C), alkyl sulfonates, aziridines,ethylenimines, methylmelamines, nitrogen mustards, nitrosoureas,antibiotics, antimetabolites, folic acid analogs (e.g., dihydrofolatereductase inhibitors such as methotrexate), purine analogs, pyrimidineanalogs, enzymes, podophyllotoxins, platinum-containing agents,interferons, and interleukins. Particular examples of knownchemotherapeutic agents which may be used in the compositions andmethods of the invention include, but are not limited to, busulfan,improsulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa,altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide, trimethylolomelamine, chlorambucil,chlornaphazine, cyclophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard,carmustine, chlorozotocin, fotemustine, lomustine, nimustine,ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol,pipobroman, aclacinomycins, actinomycin F(1), anthramycin, azaserine,bleomycin, cactinomycin, carubicin, carzinophilin, chromomycin,dactinomycin, daunorubicin, daunomycin, 6-diazo-5-oxo-1-norleucine,doxorubicin, epirubicin, mitomycin C, mycophenolic acid, nogalamycin,olivomycin, peplomycin, plicamycin, porfiromycin, puromycin,streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin,zorubicin, denopterin, methotrexate, pteropterin, trimeterxate,fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine,azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,doxifluridine, enocitabine, floxuridine, fluorouracil, tegafur,L-asparaginase, pulmozyme, aceglatone, aldophosphamide glycoside,aminolevulinic acid, amsacrine, bestrabucil, bisantrene, carboplatin,cisplatin, defofamide, demecolcine, diaziquone, elformithine,elliptinium acetate, etoglucid, etoposide, flutamide, gallium nitrate,hydroxyurea, interferon-alpha, interferon-beta, interferon-gamma,interleukin-2, lentinan, lonidamine, mitoguazone, mitoxantrone,mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinicacid, 2-ethylhydrazide, procarbazine, razoxane, sizofuran,spirogermanium, paclitaxel, tamoxifen, teniposide, tenuazonic acid,triaziquone, 2,2′,2″-trichlorotriethylamine, urethane, vinblastine,vincristine, and vindesine.

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

Toxicity and therapeutic efficacy of such therapeutic regimens may bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, for determining theLD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. The dataobtained from cell culture assays and animal studies may be used informulating a range of dosage for use in human. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED₅₀ with minimal toxicity. The dosage may vary withinthis range depending upon the dosage form employed and the route ofadministration utilized.

Processes for Making Compounds of the Invention

General procedures for preparing compounds of the invention aredescribed in the Examples, infra. In the reactions described, reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, may be protectedto avoid their unwanted participation in the reactions. Conventionalprotecting groups can be used in accordance with standard practice, forexample, see T. W. Greene and P. G. M. Wuts in “Protective Groups inOrganic Chemistry”, John Wiley and Sons, 1991.

A compound of the invention may be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention may be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Alternatively, the salt forms of the compounds of the inventionmay be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention maybe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example, a compound of the invention in anacid addition salt form may be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form may be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form may be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention may be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs may beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention may be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention may be conveniently prepared orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention may be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. Resolution of enantiomers may be carried out usingcovalent diastereomeric derivatives of the compounds of the invention,or by using dissociable complexes (e.g., crystalline diastereomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubility, reactivity, etc.) and may be readilyseparated by taking advantage of these dissimilarities. Thediastereomers may be separated by chromatography, or byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen,“Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc.,1981.

In summary, compounds having Formula (1), (2A) or (2B) may be made by aprocess which involves:

-   -   (a) general procedures as described in the Examples (infra); and    -   (b) optionally converting a compound of the invention into a        pharmaceutically acceptable salt;    -   (c) optionally converting a salt form of a compound of the        invention to a non-salt form;    -   (d) optionally converting an unoxidized form of a compound of        the invention into a pharmaceutically acceptable N-oxide;    -   (e) optionally converting an N-oxide form of a compound of the        invention to its unoxidized form;    -   (f) optionally resolving an individual isomer of a compound of        the invention from a mixture of isomers;    -   (g) optionally converting a non-derivatized compound of the        invention into a pharmaceutically acceptable prodrug derivative;        and    -   (h) optionally converting a prodrug derivative of a compound of        the invention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or may be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

The following examples are offered to illustrate but not to limit theinvention.

PREPARATION OF INTERMEDIATES Synthesis of(5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine 5

To a solution of 4-nitro-phenol 1 (36.0 mmol) in toluene (40 mL) isadded cesium carbonate (53.8 mmol) and (2-chloro-ethyl)-diethyl-aminehydrochloride (28.7 mmol). The reaction mixture is heated at 100° C. for2 h then cooled to rt. The solid is filtered under vacuum and washedwith warm toluene. The filtrate is concentrated to afforddiethyl-[2-(4-nitro-phenoxy)-ethyl]-amine 2 and used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.08 (m,2H), 6.86-6.84 (m, 2H), 4.05 (t, J=4.0 Hz, 2H), 2.81 (t, J=4.0 Hz), 2.55(q, J=8.0 Hz, 4H), 0.98 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺: 239.3.

To a solution of diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine 2 (14.0 mmol)in MeOH (20 mL), in a Parr pressure bottle, is added Pd (10% on carbon,50% wet, 10% weight). The suspension is shaken at 50 psi of H₂ for 2 h.The reaction mixture is filtered through celite. The solvent is removedand the residue is dissolved in MeOH (20 mL) and treated with HCl (1 eqof a 4N solution in dioxane) to afford4-(2-diethylamino-ethoxy)-phenylamine 3 as hydrochloride salt. ¹H NMR(400 MHz, d6-DMSO) δ 6.98-6.91 (m, 4H), 4.30 (t, J=4.0 Hz, 2H), 3.47 (t,J=4.0 Hz), 3.20 (m, 4H), 1.24 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺: 209.3.

A dry flask charged with 4-(2-diethylamino-ethoxy)-phenylamine 3 (6.1mmol), p-TSA (6.1 mmol), 5-bromo-2-chloropyrimidine 4 (6.1 mmol) in NMP(5 mL) is heated in a microwave oven at 210° C. for 15 min. The reactionmixture is diluted with water and extracted with EtOAc (5×70 mL). Theorganic layer is washed with water, brine, dried over Na₂SO₄, andconcentrated. Purification by silica chromatography(DCM:MeOH:NH₄OH=95:5:0.1) affords5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine 5. ¹HNMR (400 MHz, CDCl₃) δ 8.37 (s, 2H), 7.43-7.40 (m, 2H), 7.02 (s, 1H),6.91-6.89 (m, 2H), 4.06 (t, J=4.0 Hz, 2H), 2.90 (t, J=4.0 Hz, 2H), 2.67(q, J=8.0 Hz, 4H), 1.09 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺: 366.1.

Synthesis of2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7

Bromo-4-(difluoromethoxy)benzene 6 (2.23 g, 10 mmol), potassium acetate(30.0 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(11.0 mmol) and Pd(PPh₃)₄ (0.5 mmol) are added to a 40-mL Schlenk flaskequipped with a stir bar. The flask is evacuated and backfilled withnitrogen several times. 1,4-Dioxane (10 mL) is added by syringe. TheSchlenk flask is sealed and heated at 150° C. for 20 min in a microwaveoven. After the reaction is complete, the solvent is removed undervacuum. The residue is dissolved in DCM (200 mL) and washed with water.The organic phase is dried with anhydrous Na₂SO₄, filtered andconcentrated to yield a crude product. Purification by silica gel columnchromatography (EtOAc:hexanes, gradient from 0% to 20%) affords2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7.¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz,2H), 6.48 (t, J=73.6 Hz, 1H), 1.27 (s, 12H). MS (m/z) (M+1)⁺: 271.1.

Synthesis of sodium1-(2-(4-(5-bromopyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate13

2-(4-Nitrophenoxy)ethanol 8 (109 mmol) and Pd/C (10% wt.) are suspendedin EtOH (50 mL) and allowed to absorb 30 psi of hydrogen in a Parrshaker. The mixture is shaken at rt for 16 h. After filtration andconcentration, 2-(4-aminophenoxy)ethanol 9 is obtained as a light pinkcolored solid and used in the next step without purification. MS (m/z)(M+1)⁺: 154.1.

A mixture of 2-(4-aminophenoxy)ethanol 9 (70 mmol),5-bromo-2-chloropyrimidine 4 (70 mmol), sodium iodide (70 mmol), anddiisopropylethylamine (140 mmol) is heated at 200° C. for 15 min in amicrowave oven. The reaction mixture is poured into water (300 mL).After filtration, the solid is washed with a mixture of H₂O:MeOH=1:1(100 mL) and dried under vacuum for 12 h to give the product 10 as atannish solid which is used in the next step without purification. MS(m/z) (M+1)⁺: 310.2, 312.2.

2-(4-(5-Bromopyrimidin-2-ylamino)phenoxy)ethanol 10 (26.6 mmol) isdissolved in DCM (50 mL) followed by addition of MsCl (32 mmol). Thereaction vessel is chilled in an ice-water bath and triethylamine (53.3mmol) is added slowly. The mixture is stirred at rt for 16 h. Thesolvent is removed and the residue is triturated with water (300 mL).The solid is filtered and dried under vacuum for 12 h to give2-(4-(5-Bromopyrimidin-2-ylamino)phenoxy)ethyl methanesulfonate 11 asoff-white solid. ¹H NMR (400 MHz, d6-DMSO) δ 9.71 (s, 1H), 8.54 (s, 2H),7.59 (d, J=9.2 Hz, 2H), 6.93 (d, J=9.2 Hz, 2H), 4.52 (m, 2H), 4.22 (m,2H), 3.24 (s, 3H). MS (m/z) (M+1)⁺: 388.0, 340.0.

2-(4-(5-Bromopyrimidin-2-ylamino)phenoxy)ethyl methanesulfonate 11 (1.55mmol) and methyl isonipecotate (3.10 mmol) are dissolved in DMF (5 mL)and stirred at 90° C. for 12 h. After the reaction is completed, 2MNa₂CO₃ (20 mL) is added and the resulting mixture is extracted withEtOAc (50 mL). The organic layer is separated and concentrated to givecrude methyl1-(2-(4-(5-bromopyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate12. MS (m/z) (M+1)⁺: 435.1, 437.1.

The crude 12 is suspended in a THF/MeOH/H₂O solution (3:2:1, 10 mL) with6N aq. LiOH (9.3 mmol) and stirred at rt for 2 h. The solvent is removedunder vacuum to give an aqueous solution. To the above aqueous solution,1N NaOH (2.0 mL) is added and the precipitate is filtered and dried toyield sodium1-(2-(4-(5-bromopyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate13. ¹H NMR (400 MHz, d6-DMSO) δ 9.67 (s, 1H), 8.52 (s, 2H), 7.54 (d,J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.01 (t, J=6.0 Hz, 2H), 2.83 (m,2H), 2.61 (m, 2H), 1.98 (m, 2H), 1.60-1.81 (m, 3H), 1.42-1.58 (m, 2H).MS (m/z) (M+1)⁺: 421.1, 423.1.

Synthesis of1-(4-(5-bromopyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid 17

To a solution of 4-aminobenzyl alcohol 14 (8.12 mmol) and5-bromo-2-chloro-pyrimidine 4 (9.74 mmol) in 2-propanol (20 mL) is addedsodium iodide (8.12 mmol) and diisopropylethylamine (16.2 mmol). Thereaction mixture is heated in the microwave oven at 200° C. for 15 min.Purification by silica gel chromatography with hexane:EtOAc=7:3 affords[4-(5-bromo-pyrimidin-2-ylamino)-phenyl]-methanol 15. ¹H NMR (400 MHz,CDCl₃) δ 8.36 (s, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H)7.07 (bs, 1H), 4.60 (s, 2H). MS (m/z) (M+1)⁺: 280.3, 282.3.

To a solution of [4-(5-bromo-pyrimidin-2-ylamino)-phenyl]-methanol 15(0.94 mmol) in dioxane (2 mL) is added manganese (IV) oxide (4.7 mmol)and TBAI (0.06 mmol). The reaction mixture is heated in a microwave ovenat 130° C. for 30 min. Purification by silica gel chromatography usinghexane:EtOAc=1:1 affords4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzaldehyde 16. ¹H NMR(400 MHz, d6-DMSO) δ 10.45 (s, 1H), 9.85 (s, 1H), 8.72 (s, 2H), 7.96 (d,J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H). MS (m/z) (M+1)⁺: 278.0, 280.0.

A mixture of 4-(5-bromopyrimidin-2-ylamino)benzaldehyde 16 (5.0 mmol),isonipecotic acid methyl ester (10 mmol) and Na₂SO₄ (excess) inDCM:MeOH:DMSO (4:1:0.2 v/v, 26 mL) is stirred at rt for 1 h. ThenNaBH(OAc)₃ (15.0 mmol) is added and stirred for 12 h. The reactionmixture is quenched with 1 N HCl (1 ml). After filtration, all solventsare removed under vacuum. To the residue is added 6 N LiOH (2.5 mL) andTHF:MeOH:water (3:2:1, 6 mL). The mixture is stirred for 1 h andquenched by 12 N HCl (5 mL). After concentration, EtOH:MeCN (1:1 v/v,100 mL) is added. Inorganic solid is filtered off. The yellow filtrateis concentrated and filtered to give the HCl salt of1-(4-(5-bromopyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid 17as a yellow solid precipitate. ¹H NMR (400 MHz, d6-DMSO) δ 10.07 (s,1H), 8.63 (s, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.48 (d, J=7.6 Hz, 2H), 4.17(s, 2H), 3.10-3.40 (m, 2H), 2.89 (m, 2H), 1.67-2.06 (m, 5H). MS (m/z)(M+1)⁺: 391.1, 393.1.

Synthesis of1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid21

A mixture of 2-(4-aminophenyl)ethanol (0.72 mol),5-bromo-2-chloropyrimidine 4 (0.72 mol), sodium iodide (0.72 mol), anddiisopropylethylamine (1.45 mol) in n-butanol (400 mL) is heated atreflux for 16 h. The reaction is cooled to rt and the mixture is dilutedwith water. The light yellow solid that precipitates is filtered to give2-(4-(5-bromopyrimidin-2-ylamino)phenyl)ethanol 18. ¹H NMR (300 MHz,d6-DMSO) δ 9.72 (s, 1H), 8.52 (s, 2H), 7.55 (m, 2H), 7.09 (d, 2H), 4.64(m, 1H), 3.52 (m, 2H), 2.65 (m, 2H). MS (m/z) (M+1)⁺: 294.1, 296.1.

To a solution of 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)ethanol 18(6.22 mmol) in DCM (30 mL) is added triethylamine (9.33 mmol) andmethanesulfonyl chloride (7.47 mmol). The reaction mixture is stirred atrt for 1.5 h. The reaction is diluted with H₂O (10 mL) and washed withNa₂CO₃ solution (3×10 mL). The organic layer is washed with brine, driedover MgSO₄ and concentrated to afford4-(5-bromopyrimidin-2-ylamino)phenethyl methanesulfonate 19. ¹H NMR (400MHz, CD₂Cl₂) δ 8.36 (s, 2H), 7.65 (bs, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.14(d, J=8.4 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.79(s, 3H). MS (m/z) (M+1)⁺: 372.0, 374.0.

The reaction mixture of 4-(5-bromopyrimidin-2-ylamino)phenethylmethanesulfonate 19 (1.55 mmol) and methyl isonipecotate (3.10 mmol) inDMF (5 mL) is stirred at 90° C. for 12 h. After the reaction iscomplete, Na₂CO₃ (2.0 M, 20 mL) is added and the resulting mixture isextracted with EtOAc (50 mL). The organic layer is separated andconcentrated to give crude methyl1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate 20.MS (m/z) (M+1)⁺: 419.1.

Crude methyl1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate 20is suspended in THF/MeOH/H₂O (3:2:1, 10 mL) and 6N LiOH (9.3 mmol) andstirred at rt for 2 h. After neutralization to pH 6 by addition of HCl(1N), the solvent is removed under vacuum to give a solid which isdissolved in THF (20 mL). To the above suspension, excess Na₂SO₄ isadded and filtered. The filtrate is concentrated to yield1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid21. ¹H NMR (400 MHz, d6-DMSO) δ 9.87 (s, 1H), 9.39 (bs, 1H), 8.59 (s,2H), 7.66 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 3.58-3.64 (m, 2H),3.48-3.28 (m, 1H), 3.22-3.27 (m, 2H), 2.88-3.03 (m, 4H), 2.05-2.15 (m,2H), 1.66-1.80 (m, 2H). MS (m/z) (M+1)⁺: 405.1, 407.1.

Synthesis of2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoicacid 26

2-(4-Aminophenyl)acetic acid (4.56 mmol), 5-bromo-2-chloropyrimidine 4(3.26 mmol), and p-TSA (0.842 mmol) are heated at reflux in 1,4-dioxane(10 mL) and DMSO (2 mL) for 16 h. The mixture is poured onto water andextracted with EtOAc. Concentration of the organic phase gives2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)acetic acid 22 as a yellowsolid. ¹H NMR (400 MHz, d6-DMSO) δ 9.84 (s, 1H), 8.58 (s, 2H), 7.61 (d,J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 3.50 (s, 2H). MS (m/z) (M+1)⁺:308.0, 310.0.

2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)acetic acid 22 (5.0 mmol) andHATU (6.0 mmol) are dissolved in dry DMF (10 mL) and stirred for 10 min.Then N,O-dimethylhydroxylamine (7.5 mmol) and diisopropylethylamine(15.0 mmol) are added to the solution. The reaction mixture is stirredfor 1 h at rt. After the reaction is complete, the reaction mixture isadded dropwise into water (100 mL). The precipitate is filtered anddried to yield2-(4-(5-bromopyrimidin-2-ylamino)phenyl)-N-methoxy-N-methylacetamide 23.¹H NMR (400 MHz, d6-DMSO) δ 9.82 (s, 1H), 8.58 (s, 2H), 7.61 (d, J=8.4Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 3.67 (s, 3H), 3.34 (s, 2H), 3.10 (s,3H). MS (m/z) (M+1)⁺: 351.0, 353.0.

2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)-N-methoxy-N-methylacetamide 23(2.0 mmol), paraformaldehyde (6.0 mmol) and sodium ethoxide (12.0 mmol)are dissolved in DMSO (10 mL). The reaction mixture is stirred at rt for1 h. Then a solution of KOH (12.0 mmol) in H₂O (5.0 mL) and EtOH (5.0mL) is added. The reaction mixture is heated at 50° C. for 5 h. Afterthe reaction is completed, the reaction mixture is washed with DCM (50mL). The aqueous phase is acidified to pH ˜5 and extracted with DCM(2×50 mL). The organic layer is separated, dried and concentrated toyield 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)-3-hydroxypropanoic acid25, which is used in the next step without further purification. ¹H NMR(400 MHz, d6-DMSO) δ 12.30 (bs, 1H), 9.84 (s, 1H), 8.57 (s, 2H), 7.61(d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 3.90 (t, J=8.8 Hz, 1H),3.49-3.61 (m, 2H), 3.35 (bs, 1H). MS (m/z) (M+1)⁺: 338.0, 340.0.

To a solution of2-(4-(5-bromopyrimidin-2-ylamino)phenyl)-3-hydroxypropanoic acid 25 (0.5mmol) in 1,4-dioxane (2 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(0.5 mmol), Na₂CO₃ (1.5 mmol of a 3.0 M aq. solution) and Pd(PPh₃)₄(0.025 mmol). The reaction is evacuated and backfilled with nitrogentwice then heated at 150° C. for 10 min. The reaction mixture is dilutedwith water (10 mL). The aqueous layer is washed with DCM (2×50 mL) andacidified to pH 5 using aqueous HCl (1 N). The resulting mixture isextracted with DCM (2×50 mL). The organic layer is separated, dried overNa₂SO₄ and concentrated to yield a crude2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoicacid 26 which is used without further purification. ¹H NMR (400 MHz,d6-DMSO) δ 9.65 (s, 1H), 8.79 (s, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.60 (d,J=8.4 Hz, 2H), 7.30 (s, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz,2H), 3.60-3.70 (m, 2H), 3.50-3.58 (m, 2H), 3.20-3.26 (m, 2H). MS (m/z)(M+1)⁺: 402.1.

Synthesis of-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine29a

5-Bromo-2-chloropyrimidine 4 (50 mmol), 4-methyl-3-nitroaniline (60mmol) and methylsulphonic acid (15 mmol) are heated at reflux in1,4-dioxane (100 mL) for 16 h. The mixture is poured into water,filtered and dried under vacuum to give5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27 as a yellowsolid. ¹H NMR (400 MHz, d6-DMSO) δ 10.25 (s, 1H), 8.68 (s, 2H), 8.49 (d,J=2.0 Hz, 1H), 7.86 (dd, J=2.4, 8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H),2.46 (s, 3H). MS (m/z) (M+1)⁺: 309.0, 311.0.

To a solution of 5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27(0.5 mmol) in 1,4-dioxane (2.0 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(0.5 mmol), Na₂CO₃ (1.5 mmol of a 3.0 M aq. solution) and Pd(PPh₃)₄(0.025 mmol). The reaction is evacuated and backfilled with nitrogentwice then heated in the microwave oven at 150° C. for 10 min. Thereaction mixture is diluted with water (10 mL) and extracted with DCM(2×50 mL). The organic layer is separated, dried over Na₂SO₄ andconcentrated. Purification by preparative HPLC (ACN gradient 10-70%)affords4-(difluoromethoxy)phenyl)-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine28a. ¹H NMR (400 MHz, d6-DMSO) δ 10.23 (s, 1H), 8.92 (s, 2H), 8.66 (d,J=2.4 Hz, 1H), 7.93 (dd, J=2.4, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H),7.43 (d, J=8.4 Hz, 1H), 7.31 (t, J=74.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H),2.47 (s, 3H). MS (m/z) (M+1)⁺: 373.1.

A suspension of5-(4-(difluoromethoxy)phenyl)-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine28a (1.5 mmol) and SnCl₂.2H₂O (4.5 mmol) in 1N NaHSO₄ (50 mL) and1,4-dioxane (50 mL) is heated at 100° C. for 1 h. The solvent is removedunder vacuum and the residue dissolved in 5% NaOH and extracted with DCM(3×50 mL). The organic layer is washed with 5% NaOH (1×50 mL), water(1×50 mL), brine, dried over Na₂SO₄ and concentrated to affordN1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine29a which is used without further purification. ¹H NMR (400 MHz,d6-DMSO) δ 9.44 (s, 1H), 8.76 (s, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.27 (d,J=8.8 Hz, 2H), 7.30 (t, J=74.4 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.90(dd, J=2.0, 8.0 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.95 (bs, 2H), 2.02 (s,3H). MS (m/z) (M+1)⁺: 343.1.

Synthesis of4-methyl-N1-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-yl)benzene-1,3-diamine29b

To a solution of 5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27(9.7 mmol) in 1,4-dioxane (29 mL) is added4-(trifluoromethoxy)phenylboronic acid (10.7 mmol), Na₂CO₃ (29.2 mmol of1.8 M aq. solution) and Pd(PPh₃)₄ (1.46 mmol). The reaction is evacuatedand backfilled with nitrogen twice then heated at 100° C. for 12 h. Thereaction mixture is diluted with water (20 mL) and extracted with EtOAc(2×50 mL). The organic layer is separated, dried over Na₂SO₄ andconcentrated. Purification by preparative HPLC (ACN gradient 10-70%)affordsN-(4-methyl-3-nitrophenyl)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine28b. MS (m/z) (M+1)⁺: 390.1.

N-(4-methyl-3-nitrophenyl)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine28b (7.53 mmol) and SnCl₂.2H₂O (33.2 mmol) are suspended in 6N HCl (40mL). The mixture is heated at 100° C. for 3 h. The reaction vessel ischilled in an ice-water bath and 5% NaOH is added. The organic layer isextracted with EtOAc (3×50 mL), washed with brine (1×50 mL), dried overNa₂SO₄ and concentrated to afford4-methyl-N1-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-yl)benzene-1,3-diamine29b which is used without further purification. ¹H NMR (400 MHz,d6-DMSO) δ 9.54 (s, 1H), 8.84 (s, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.51 (d,J=8.0 Hz, 2H), 7.12 (d, J=2.4 Hz, 1H), 6.94 (dd, J=2.0 and 8.0 Hz, 1H),6.88 (d, J=8.4 Hz, 1H), 4.83 (bs, 2H), 2.07 (s, 3H). MS (m/z) (M+1)⁺:361.1.

Synthesis of 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30

To a solution of 5-bromo-2-chloropyrimidine 4 (7.7 mmol) in 1,4-dioxane(1.5 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(8.9 mmol), 1.8M K₂CO₃ aq. (16.2 mmol) and Pd(PPh₃)₄ (0.38 mmol). Thereaction is evacuated and backfilled with nitrogen twice then heated at150° C. for 10 min under microwave. After this time, the reactionmixture is diluted with a saturated solution of NH₄Cl and extracted withDCM (3×50 mL). The organic layer is washed with brine, dried over Na₂SO₄and concentrated. Purification by short silica gel chromatography usinga hexane:EtOAc=3:1 mixture affords2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30. ¹HNMR (400 MHz,CDCl₃) δ 8.73 (s, 2H), 7.47-7.52 (m, 2H), 7.20-7.24 (m, 2H), 6.52 (t,J=72 Hz, 1H). MS (m/z) (M+1)⁺: 257.0.

Synthesis of2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoicacid 26

A mixture of ethyl 2-(4-aminophenyl)acetate (8 mmol),2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30 (4 mmol), and p-TSA(2 mmol) in 1,4-dioxane (4 mL) are heated at reflux for 4 h. The mixtureis poured onto 1 N HCl. The solid is filtered, washed with 1 N HCl anddried to afford ethyl2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)acetate 31as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 2H), 7.92 (s, 1H),7.54 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H),7.18 (d, J=9.1 Hz, 2H), 6.49 (t, J=73.5 Hz, 1H), 4.09 (q, J=7.1 Hz, 2H),3.54 (s, 2H), 1.19 (t, J=7.1 Hz, 3H). MS (m/z) (M+1)⁺: 400.1.

Ethyl2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)acetate 31(1 mmol) and paraformaldehyde (5 mmol.) are dissolved in dry DMSO(0.2-0.5M) and heated at 70° C. in the presence of Na₂CO₃ (5 mmol.) for2-6 h until greater than 50% conversion is achieved by LC/MS monitoring.The mixture is diluted with EtOAc and washed with water. Afterconcentration, the residue is purified by silica gel chromatography toyield ethyl2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoate32. MS (m/z) (M+1)⁺: 432.1.

To a solution of ethyl2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoate32 (1 mmol) in THF:MeOH:water (3:2:1 v/v) is added 6 N LiOH (3 mmol).The reaction mixture is stirred at rt for 1 h until complete by LC/MSand diluted with water. The aqueous layer is washed with DCM (2×30 mL)and acidified to pH=5 using aqueous 1N HCl. The resulting mixture isextracted with DCM (3×50 mL). The organic layer is separated, dried overNa₂SO₄ and concentrated to yield a crude product, which uponcrystallization from water yield2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoicacid, 26 as off white solid. ¹H NMR (400 MHz, d6-DMSO) δ 9.65 (s, 1H),8.79 (s, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.30 (s,1H), 7.27 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 3.60-3.70 (m, 2H),3.50-3.58 (m, 2H), 3.20-3.26 (m, 2H). MS (m/z) (M+1)⁺: 402.1.

Chiral HPLC separation using a (R,R)-WelkO-1 column andhexane:ethanol:methanol=75:12.5:12.5 0.1% diethylamine as gradientaffords the two enantiomers 26a (first peak eluted) and 26b (second peakeluted). The enantiomer 26a is arbitrarily assigned the R configurationwhereas enantiomer 26b is arbitrarily assigned the S configuration.

Synthesis of 2-(trifluoromethyl)piperazine 35a

A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one 32 (38.4 mmol) andNaOAc (153.7 mmol) in H₂O (50 mL) is heated at 100° C. for 12 h.Extraction of aqueous mixture with EtOAc (2×50 mL) and concentration oforganic phase affords a crude oil. To the above residue is added DMF (30mL), and the solution is cooled to 0° C. Then a solution ofN1-benzylethane-1,2-diamine (2.3 mL) in DMF (15 mL) is added. Theresulting reaction mixture is stirred at rt for 12 h. Solvent is removedunder vacuum to afford a residue which is dissolved in THF (15 mL) andcitrate buffer (30 mL), followed by addition of 1M NaBH₃CN (25 mL). Themixture is stirred at rt for 12 h. The organic solvent is removed undervacuum and the resulting residue is basified to pH=8 by addition of 1NNaOH. Extraction of aqueous solution with DCM (2×50 mL) andconcentration of the organic phase yield a crude oil which is purifiedby silica gel chromatography using a hexane:EtOAc=3:1 to afford1-benzyl-3-(trifluoromethyl)piperazine 34a. ¹H NMR (400 MHz, d2-DCM) δ7.37-7.25 (m, 5H), 3.57 (d, 2H), 3.35-3.45 (m, 1H), 3.05-3.10 (m, 1H),2.87-3.00 (m, 2H), 2.74-2.80 (m, 1H), 2.10-2.18 (m, 2H), 1.74 (s, 1H).MS (m/z) (M+1)⁺: 245.1.

1-Benzyl-3-(trifluoromethyl)piperazine 34a (4.1 mmol) is dissolved inMeOH (50 mL) followed by addition of AcOH (2.0 mL) and 5% mol of Pd/C.The flask is charged with a hydrogen balloon and stirred for 12 h. Themixture is filtered over celite and the filtrate is concentrated toafford 2-(trifluoromethyl)piperazine 35a, which is used without furtherpurification. MS (m/z) (M+1)⁺: 155.1.

Synthesis of Ethyl 2-(trifluoromethyl)piperazine-1-carboxylate 35b

To a solution of 1-benzyl-3-(trifluoromethyl)piperazine 34a (1.0 mmol)and pyridine (1.1 mmol) in DCM (5 mL), is added ethyl chloroformate (1.1mmol). The resulting mixture is stirred at rt for 1 h. After thereaction is complete, the reaction mixture is diluted with DCM (15 mL)and washed with water. The organic layer is separated, dried overNa₂SO₄, filtered, and concentrated to afford ethyl4-benzyl-2-(trifluoromethyl)piperazine-1-carboxylate 34b, which is usedwithout purification. MS (m/z) (M+1)⁺: 317.1.

Ethyl 4-benzyl-2-(trifluoromethyl)piperazine-1-carboxylate 34b (1.0mmol) is dissolved in MeOH (10 mL) followed by addition of AcOH (1.0 mL)and 5% mol of Pd/C. The flask is charged with a hydrogen balloon andstirred for 12 h. The mixture is filtered over celite and the filtrateis concentrated to afford 2-(trifluoromethyl)piperazine 1-carboxylate35b, which is used without further purification. MS (m/z) (M+1)⁺: 227.1.

Preparation of Final Compounds

Type A Compounds

Example A1N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine

To a solution of(5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine 5 (0.5mmol) in 1,4-dioxane (2.0 mL) is added 4-(trifluoromethoxy)phenylboronicacid (0.5 mmol), 3M Na₂CO₃ (1.5 mmol) and Pd(PPh₃)₄ (0.025 mmol). Thereaction is evacuated and backfilled with nitrogen twice then heated at150° C. for 10 min. Purification by preparative HPLC (ACN gradient10-70%) affordsN-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amineA1. MS (m/z) (M+1)⁺: 447.2.

Example A2N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine

To a solution of(5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine 5 (0.5mmol) in 1,4-dioxane (2.0 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(0.5 mmol), 3M Na₂CO₃ (1.5 mmo) and Pd(PPh₃)₄ (0.025 mmol). The reactionis evacuated and backfilled with nitrogen twice then heated at 150° C.for 10 min. Purification by preparative HPLC (ACN gradient 10-70%)affordsN-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-(difluoromethoxy)phenyl)pyrimidin-2-amineA2. ¹H NMR (400 MHz, d6-DMSO) δ 9.68 (s, 1H), 8.78 (s, 2H), 7.76 (d,J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 2H), 7.28 (t, J=74.0 Hz, 1H), 7.27 (d,J=8.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 3.51 (m,2H), 3.23 (m, 4H), 1.24 (t, J=7.2, 6H). MS (m/z) (M+1)⁺: 429.2.

Example A31-(2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid

To a solution of sodium1-(2-(4-(5-bromopyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate13 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(0.05 mmol), 3M Na₂CO₃ (0.15 mmol) and Pd(PPh₃)₄ (0.0025 mmol). Thereaction is evacuated and backfilled with nitrogen twice then heated at150° C. for 10 min. Purification by prep-HPLC (ACN gradient 10-70%)affords1-(2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid A3. ¹H NMR (400 MHz, d6-DMSO) δ 9.68 (s, 1H), 8.78 (s, 2H), 7.76(d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 2H), 7.28 (t, J=74.0 Hz, 1H), 7.27(d, J=8.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 3.51(m, 2H), 3.23 (m, 4H), 1.24 (t, J=7.2, 6H). MS (m/z) (M+1)⁺: 485.2.

Example A41-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylicacid

To a solution of1-(4-(5-bromopyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid 17(0.05 mmol) in 1,4-dioxane (1.0 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(0.05 mmol), 3M Na₂CO₃ (0.15 mmol) and Pd(PPh₃)₄ (0.0025 mmol). Thereaction is evacuated and backfilled with nitrogen twice then heated at150° C. for 10 min. Purification by preparative HPLC (ACN gradient10-70%) affords1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylicacid A4. ¹H NMR (400 MHz, d4-MeOH) δ 8.64 (s, 2H), 7.78 (d, J=8.8 Hz,2H), 7.56 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz,2H), 6.78 (t, J=74.0 Hz, 1H), 4.11 (s, 2H), 3.31 (m, 2H), 2.92 (m, 2H),2.36 (m, 1H), 2.02 (m, 2H), 1.81 (m, 2H). MS (m/z) (M+1)⁺: 455.2.

Example A51-(4-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylicacid

To a solution of1-(4-(5-bromopyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid 17(0.05 mmol) in 1,4-dioxane (1.0 mL) is added4-(trifluoromethoxy)phenylboronic acid (0.05 mmol), 3M Na₂CO₃ (0.15mmol) and Pd(PPh₃)₄ (0.0025 mmol). The reaction is evacuated andbackfilled with nitrogen twice then heated at 150° C. for 10 min.Purification by preparative HPLC (ACN gradient 10-70%) affords1-(4-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylicacid A5. ¹H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.89 (s, 2H), 7.88(M, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.23 (s, 2H),2.95 (m, 1H), 2.51 (m, 4H), 2.09 (m, 2H), 1.71 (m, 2H). MS (m/z) (M+1)⁺:473.2.

Example A61-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid

To a solution of1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid21 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(0.05 mmol), 3M Na₂CO₃ (0.15 mmol) and Pd(PPh₃)₄ (0.0025 mmol). Thereaction is evacuated and backfilled with nitrogen twice then heated ina microwave oven at 150° C. for 10 min. Purification by preparative HPLC(ACN gradient 10-70%) affords1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid A6. MS (m/z) (M+1)⁺: 469.2.

Type B Compounds

Example B1N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-methylpiperidine-2-carboxamide

N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine29a (0.1 mmol), 1-methylpiperidine-2-carboxylic acid (0.1 mmol) and HATU(0.15 mmol) are dissolved in dry DMF (0.5 mL) at rt.Diisopropylethylamine (0.50 mmol) is added to the solution. The reactionmixture is stirred for 1 h at rt. HPLC purification affords the targetcompound B1 as a TFA salt. MS (m/z) (M+1)⁺: 468.2.

Example B4(R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide

Similar to the preparation of B1. ¹H NMR (400 MHz, d6-DMSO) δ 9.76 (s,1H), 9.47 (s, 1H), 8.81 (s, 2H), 7.95 (s, 1H), 7.77 (m, 3H), 7.55 (dd,J=2.0, 8.8 Hz, 1H), 7.29 (t, J=74.4 Hz, 1H), 7.27 (d, J=9.2 Hz, 2H),7.13 (d, J=8.4 Hz, 1H), 4.26 (m, 1H), 2.40 (m, 2H), 2.14 (s, 3H), 2.04(m, 2H). MS (m/z) (M+1)⁺: 454.2.

Example B5N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-oxopiperidine-3-carboxamide

Similar to the preparation of B1. ¹H NMR (400 MHz, d6-DMSO) δ 9.75 (s,1H), 9.50 (s, 1H), 8.81 (s, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.74 (d, J=2.0Hz, 1H), 7.56 (m, 2H), 7.30 (t, J=74.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H),7.13 (d, J=8.4 Hz, 1H), 3.34 (m, 2H), 2.86 (m, 1H), 2.25 (m, 2H), 2.12(s, 3H), 2.03 (m, 1H), 1.92 (m, 1H). MS (m/z) (M+1)⁺: 468.2.

Example B6N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-fluoropyridine-3-carboxamide

Similar to the preparation of B1. ¹H NMR (400 MHz, d6-DMSO) δ 10.21 (s,1H), 9.85 (s, 1H), 8.88 (s, 1H), 8.55 (m, 1H), 7.86 (s, 1H), 7.79 (d,J=8.8 Hz, 2H), 7.64 (dd, J=2.0, 8.4 Hz, 1H), 7.40 (dd, J=2.4, 8.4 Hz,1H), 7.31 (t, J=74.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.4 Hz,1H), 2.21 (s, 3H). MS (m/z) (M+1)⁺: 466.1.

Example B7N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1H-imidazole-5-carboxamide

N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine29a (0.1 mmol) and 5H,10H-diimidazo[1,5-a:1′,5′-d]pyrazine-5,10-dione(0.1 mmol) in dry DMF (0.5 mL) are heated at 110° C. for 24 h. HPLCpurification affords the target compound B7 as a TFA salt. ¹H NMR (400MHz, d6-DMSO) δ 9.80 (s, 2H), 8.81 (s, 2H), 8.44 (s, 1H), 8.04 (s, 2H),7.77 (d, J=8.8 Hz, 2H), 7.57 (m, 1H), 7.28 (t, J=74.0 Hz, 1H), 7.27 (d,J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 2.20 (s, 3H). MS (m/z) (M+1)⁺:437.2.

Example B8 (S)-N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide

4-Methyl-N1-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-yl)benzene-1,3-diamine29b (0.1 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.1 mmol) andHATU (0.15 mmol) are dissolved in dry DMF (0.5 mL) at rt.Diisopropylethylamine (0.50 mmol) is added to the solution and thereaction mixture is stirred for 1 h at rt. HPLC purification affords thetarget compound B8 as a TFA salt. MS (m/z) (M+1)⁺: 473.1.

Example B9N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-cyclopropyl-5-oxopyrrolidine-3-carboxamide

Similar to the preparation of B1. ¹H NMR (400 MHz, d4-MeOD) δ 8.84 (s,2H), 7.71 (m, 3H), 7.36 (s, 2H), 7.29 (d, J=8.0 Hz, 2H), 6.91 (t, J=74.0Hz, 1H), 3.52-3.56 (m, 2H), 3.46 (m, 1H), 2.74 (m, 2H), 2.64 (m, 1H),2.29 (s, 3H), 0.77 (m, 4H). MS (m/z) (M+1)⁺: 494.2.

Example B10N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-ethyl-6-oxopiperidine-3-carboxamide

Similar to the preparation of B1. ¹H NMR (400 MHz, d6-DMSO) δ 9.75 (s,1H), 9.52 (s, 1H), 8.79 (s, 2H), 7.76 (m, 3H), 7.55 (m, 1H), 7.28 (d,J=8.0 Hz, 2H), 7.27 (t, J=74.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 3.2-3.5(m, 2H), 2.9-3.0 (m, 1H), 2.5 (m, 2H), 2.3 (m, 2H), 2.13 (s, 3H),1.80-2.08 (m, 2H), 1.05 (t, J=6.8 Hz, 3H). MS (m/z) (M+1)⁺: 496.2.

Type C Compounds

Example C1 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-N-(2-fluoroethyl)-3-hydroxypropanamide

2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoicacid 26 (0.1 mmol), 2-fluoroethanamine (0.1 mmol) and HATU (0.15 mmol)are dissolved in dry DMF (0.5 mL) at rt. Diisopropylethylamine (0.50mmol) is added to the solution. The reaction mixture is stirred for 1 hat rt. HPLC purification (ACN gradient 10-90%) affords2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-N-(2-fluoroethyl)-3-hydroxypropanamideC1 as a TFA salt. MS (m/z) (M+1)⁺: 447.2.

Example C22-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one

Similar to the preparation of C1. ¹H NMR (400 MHz, d4-MeOH) δ 8.88 (d,J=2.8 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.59 (t, J=8.8 Hz, 2H), 7.43 (m,2H), 7.31 (d, J=8.4 Hz, 2H), 6.92 (t, J=74.0 Hz, 1H), 4.20 (m, 2H), 4.13(m, 1H), 3.80 (m, 2H), 3.70 (m, 2H), 1.56 (m, 2H), 1.50 (m, 2H), 1.28(m, 1H). MS (m/z) (M+1)⁺: 485.2.

Example C3 (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-oneExample C4(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one

Similar to the preparation of C1. Chiral separation on (R,R)-WelkO-1column and hexane:isopropanol=70:30 as gradient affords the twoenantiomers C3 (first peak eluted) and C4 (second peak eluted). C3 isarbitrarily assigned the R configuration. ¹H NMR (400 MHz, d4-MeOH) δ8.88 (d, J=2.8 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.59 (t, J=8.8 Hz, 2H),7.43 (m, 2H), 7.31 (d, J=8.4 Hz, 2H), 6.92 (t, J=74.0 Hz, 1H), 4.20 (m,2H), 4.13 (m, 1H), 3.80 (m, 2H), 3.70 (m, 2H), 1.56 (m, 2H), 1.50 (m,2H), 1.28 (m, 1H). MS (m/z) (M+1)⁺: 485.2.

C4 is arbitrarily assigned the S configuration. ¹H NMR (400 MHz,d4-MeOH) δ 8.88 (d, J=2.8 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.59 (t,J=8.8 Hz, 2H), 7.43 (m, 2H), 7.31 (d, J=8.4 Hz, 2H), 6.92 (t, J=74.0 Hz,1H), 4.20 (m, 2H), 4.13 (m, 1H), 3.80 (m, 2H), 3.70 (m, 2H), 1.56 (m,2H), 1.50 (m, 2H), 1.28 (m, 1H). MS (m/z) (M+1)⁺: 485.2.

Example C5 (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide

2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoicacid 26a (0.1 mmol), (R)-1-aminopropan-2-ol (0.1 mmol) and HATU (0.12mmol) are dissolved in dry DMF (0.5 mL) at rt. Diisopropylethylamine(0.40 mmol) is added and the reaction mixture is stirred for 1 h at rt.HPLC purification (ACN gradient 10-70%) affords(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamideC5 as a TFA salt. ¹H NMR (400 MHz, d6-DMSO) δ 9.73 (s, 1H), 8.80 (s,2H), 7.92 (t, J=8.0 Hz, 1H), 7.77 (m, 2H), 7.30 (t, J=74.0 Hz, 1H), 7.28(m, 2H), 7.22 (m, 2H), 7.45 (t, J=4.0 Hz, 1H), 3.91 (m, 1H), 3.59 (m,2H), 3.40 (quint., J=8.0 Hz, 1H), 0.95 (d, J=8.0 Hz, 3H). MS (m/z)(M+1)⁺: 459.2.

Example C6(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide

2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoicacid 26b (0.1 mmol), (R)-1-aminopropan-2-ol (0.1 mmol) and HATU (0.12mmol) are dissolved in dry DMF (0.5 mL) at rt. Diisopropylethylamine(0.40 mmol) is added to the solution. The reaction mixture is stirredfor 1 h at rt. HPLC purification (ACN gradient 10-70%) affords(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamideC6 as a TFA salt. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s, 1H), 8.80 (s,2H), 7.93 (m, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.28(t, J=72.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 3.93(m, 1H), 3.61 (m, 1H), 2.99 (m, 2H), 2.51 (m, 2H), 0.95 (d, J=6.0 Hz,3H). MS (m/z) (M+1)⁺: 459.1.

Example C7 (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide

Similar to the preparation of C5. ¹H NMR (400 MHz, d4-MeOH) δ 8.69 (s,2H), 7.67 (m, 4H), 7.31 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 6.88(t, J=76.0 Hz, 1H), 4.62 (s, 1H), 4.14 (m, 1H), 3.83 (m, 1H), 3.70 (m,2H), 3.26 (dd J=8.0, 12.0 hz, 1H), 3.10 (dd, J=8.0, 12.0 Hz, 1H), 1.09(d, J=4.0 Hz, 3H). MS (m/z) (M+1)⁺: 459.1.

Example C8(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide

Similar to the preparation of C6. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s,1H), 8.80 (s, 2H), 7.93 (m, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.23 (t, J=76 Hz, 1H), 7.21 (d, J=8 Hz,2H), 7.16 (d, J=8.4 Hz, 2H), 3.84 (m, 1H), 3.42 (m, 3H), 3.28 (m, 1H),1.72 (m, 3H), 1.02 (m, 6H). MS (m/z) (M+1)⁺: 459.1.

Example C9 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide

Similar to the preparation of C1. ¹H NMR (400 MHz, d6-DMSO) δ 9.70 (s,1H), 8.79 (s, 2H), 8.13 (s, 1H), 7.93 (d, J=2.1 Hz, 2H), 7.77 (d, J=8.5Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.28 (d, J=8 Hz, 2H), 7.26 (t, J=75 Hz,1H), 7.23 (d, J=8.4 Hz, 2H), 3.92 (dt, J=8.7, 2.5 Hz, 1H), 3.0 (m, 2H),2.5 (m, 5H), 2.07 (s, 1H), 0.96 (t, J=5.7 Hz, 3H). MS (m/z) (M+1)⁺:459.1.

Example C11 (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide

Similar to the preparation of C5. ¹H NMR (400 MHz, d6-DMSO) δ 9.73 (s,1H), 8.80 (s, 2H), 7.93 (m, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4Hz, 2H), 7.29 (t, J=76.0 Hz, 1H), 7.27 (d, J=8 Hz, 2H), 7.23 (d, J=8.4Hz, 2H), 3.93 (m, 1H), 3.59 (m, 1H), 3.0 (m, 2H), 2.51 (m, 2H), 0.97 (d,J=6 Hz, 3H). MS (m/z) (M+1)⁺: 499.1.

Example C12 (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide

Similar to the preparation of C6. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s,1H), 8.80 (s, 2H), 8.14 (s, 1H), 7.79 (m, 3H), 7.66 (d, J=8.4 Hz, 2H),7.29 (d, J=7.6 Hz, 2H), 7.27 (t, J=79.6 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H),3.91 (m, 1H), 2.51 (m, 4H), 1.76 (m, 2H), 1.62 (m, 1H), 1.19 (m, 5H). MS(m/z) (M+1)⁺: 499.2.

Example C13 (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide

Similar to the preparation of C5. ¹H NMR (400 MHz, d6-DMSO) δ 9.74 (s,1H), 8.81 (s, 2H), 7.84 (m, 1H), 7.78 (m, 2H), 7.68 (m, 2H), 7.30 (t,J=76.0 Hz, 1H), 7.27 (d, J=8 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 4.73 (t,J=4.0 Hz, 1H), 4.37 (d, J=4.0 Hz, 1H), 3.93 (m, 1H), 3.65 (bm, 1H), 3.58(m, 2H), 3.48 (m, 1H), 1.62 (m, 2H), 1.38 (m, 8H). MS (m/z) (M+1)⁺:499.1.

Example C14(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide

Similar to the preparation of C6. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s,1H), 8.8 (s, 2H), 7.83 (d, J=7.6 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.66(d, J=8.4 Hz, 2H), 7.27 (d, J=7.6 Hz, 2H), 7.26 (t, J=79.6 Hz, 1H), 7.22(d, J=8.4 Hz, 2H), 3.91 (m, 1H), 3.58 (m, 1H), 2.51 (m, 4H), 1.59 (m,2H), 1.46 (m, 5H). MS (m/z) (M+1)⁺: 499.2.

Example C152-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4s)-4-hydroxycyclohexyl)propanamide

Similar to the preparation of C1. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s,1H), 8.8 (s, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.29(d, J=74 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 3.91(t, J=9 Hz, 1H), 3.6 (m, 2H), 2.51 (m, 3H), 1.46 (m, 9H). MS (m/z)(M+1)⁺: 499.4.

Example C18(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one

Similar to the preparation of C5. ¹H NMR (400 MHz, d6-DMSO) δ 9.75 (s,1H), 8.82 (s, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.70 (m, 2H), 7.28 (t, J=70.0Hz, 1H), 7.27 (m, 4H), 4.32 (m, 1H), 4.20 (m, 1H), 3.95 (m, 2H), 3.74(m, 1H), 2.91 (m, 1H), 1.90 (m, 2H), 1.68 (m, 1H), 1.41 (m, 2H). MS(m/z) (M+1)⁺: 485.1.

Example C19(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one

Similar to the preparation of C6. ¹H NMR (400 MHz, d6-DMSO) δ 9.76 (d,J=10.8 Hz, 1H), 8.82 (s, 2H), 7.77 (d, J=7.6 Hz, 2H), 7.71 (m, 2H), 7.28(t, J=67.6 Hz, 1H), 7.27 (d, J=6.8 Hz, 2H), 3.95 (m, 2H), 2.92 (m, 1H),2.55 (m, 6H), 2.53 (m, 2H), 1.68 (m, 1H), 1.37 (m, 2H). MS (m/z) (M+1)⁺:485.1.

Example C21(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one

Similar to the preparation of C6. ¹H NMR (400 MHz, d6-DMSO) δ 9.77 (s,1H), 8.82 (s, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.71 (m, 2H), 7.28 (t, J=68Hz, 1H), 7.27 (d, J=6.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 3.95 (m, 2H),2.92 (m, 1H), 2.55 (m, 6H), 2.53 (m, 2H), 1.68 (m, 1H), 1.37 (m, 2H). MS(m/z) (M+1)⁺: 485.1.

Example C22(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one

Similar to the preparation of C5. ¹H NMR (400 MHz, d4-MeOH) δ 8.68 (s,2H), 7.58 (m, 4H), 7.22 (m, 4H), 6.79 (t, J=72.0 Hz, 1H), 4.20 (m, 1H),4.01 (m, 2H), 3.93 (m, 1H), 3.59 (bm, 2H), 3.38 (m, 1H), 3.33 (m, 1H),3.06 (m, 1H), 2.72 (m, 1H), 2.64 (m, 1H). MS (m/z) (M+1)⁺: 485.1.

Example C24 (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide

Similar to the preparation of C5. ¹H NMR (400 MHz, d6-DMSO) δ 9.71 (s,1H), 8.79 (s, 2H), 7.09 (d, J=6.8 Hz, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.67(d, J=8.0 Hz, 2H), 7.28 (t, J=71.6 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.22(d, J=8.0 Hz, 2H), 3.92 (m, 1H), 3.85 (m, 1H), 3.75 (m, 1H), 1.88 (m,1H), 1.78 (m, 1H), 1.53 (m, 2H), 1.43 (m, 1H), 1.24 (m, 2H). MS (m/z)(M+1)⁺: 485.1.

Example C27 (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide

Similar to the preparation of C6. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s,1H), 8.8 (s, 2H), 7.89 (d, J=6.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.66(d, J=8.4 Hz, 2H), 7.29 (t, J=74.4 Hz, 1H) 7.27 (d, J=7.2 Hz, 2H), 7.22(d, J=8.4 Hz, 2H), 3.91 (m, 1H), 3.73 (m, 2H), 1.99 (m, 3H), 1.65 (m,3H), 1.38 (m, 2H). MS (m/z) (M+1)⁺: 485.1.

Example C28 (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide

Similar to the preparation of C6. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s,1H), 8.8 (s, 2H), 7.89 (d, J=6.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.66(d, J=8.4 Hz, 2H), 7.29 (t, J=74.4 Hz, 1H) 7.27 (d, J=7.2 Hz, 2H), 7.22(d, J=8.4 Hz, 2H), 3.89 (m, 2H), 3.74 (m, 1H), 1.99 (m, 2H), 1.87 (m,1H), 1.79 (m, 1H), 1.57 (m, 2H), 1.43 (m, 1H), 1.19 (m, 1H). MS (m/z)(M+1)⁺: 485.2.

Example C29(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide

Similar to the preparation of C6. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s,1H), 8.8 (s, 2H), 7.89 (d, J=6.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.66(d, J=8.4 Hz, 2H), 7.29 (t, J=74.4 Hz, 1H) 7.27 (d, J=7.2 Hz, 2H), 7.22(d, J=8.4 Hz, 2H), 3.97 (m, 2H), 3.80 (m, 1H), 1.99 (s, 2H), 1.71 (m,3H), 1.54 (m, 1H), 1.41 (m, 2H). MS (m/z) (M+1)⁺: 485.1.

Example C30(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide

Similar to the preparation of C5. ¹H NMR (400 MHz, d4-MeOH) δ 8.68 (s,2H), 7.56 (m, 4H), 7.22 (m, 4H), 6.77 (t, J=72.0 Hz, 1H), 4.01 (m, 1H),3.84 (m, 1H), 3.81 (m, 1H), 3.57 (m, 2H),), 2.01 (m, 1H), 1.74 (m, 1H),1.69 (m, 2H), 1.44 (m, 2H). MS (m/z) (M+1)⁺: 485.1.

Example C31(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide

Similar to the preparation of C5. ¹H NMR (400 MHz, d6-DMSO) δ 9.71 (s,1H), 8.80 (s, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.53(d, J=7.2 Hz, 1H), 7.27 (t, J=65.6 Hz, 1H) 7.26 (m, 4H), 3.90 (m, 4H),3.65 (m, 1H), 1.79 (m, 1H), 1.70 (m, 2H), 1.52 (m, 3H). MS (m/z) (M+1)⁺:485.2.

Example C322-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one

2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-oneC32 is obtained as a minor side product during the preparation ofExample C2. ¹H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.85 (s, 2H), 7.2(m, 4H), 7.35 (m, 4H), 7.29 (t, J=74.0 Hz, 1H), 5.70 (s, 1H), 5.11 (s,1H), 4.06 (m, 1H), 3.70 (m, 1H), 3.15 (m, 2H), 1.78 (m, 1H), 1.58 (m,1H), 1.35 (m, 1H), 1.16 (m, 1H). MS (m/z) (M+1)⁺: 467.2.

Example C33 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)ethanone

2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)ethanoneC33 is obtained as a minor side product during the preparation ofExample C2. ¹H NMR (400 MHz, d6-DMSO) δ 9.76 (s, 1H), 8.81 (s, 2H), 7.77(d, J=8.2 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.29 (t, J=71 Hz, 1H), 7.28(d, J=7.4 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 3.94 (dd, J=6.2, 4.1 Hz, 1H),3.73 (dd, J=8.4, 5.3 Hz, 1H), 3.64 (m, 2H), 3.15 (dd, J=10.6, 8.6 Hz,1H), 2.97 (m, 1H), 1.62 (m, 2H), 1.2 (m, 4H). MS (m/z) (M+1)⁺: 455.2.

Example C35 (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-oneExample C36 (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one

Similar to the preparation of C1. Chiral HPLC separation on(R,R)-WelkO-1 column and hexane:isopropanol=70:30 as gradient affordsthe two enantiomers C35 (first peak eluted) and C36 (second peakeluted). C35 is arbitrarily assigned the R configuration. ¹H NMR (400MHz, d6-DMSO) δ 9.80 (s, 1H), 8.81 (s, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.72(d, J=8.0 Hz, 2H), 7.1-7.5 (m, 5H), 4.09 (s, 1H), 3.96 (t, J=8.8 Hz,1H), 2.7-2.9 (m, 2H), 2.55 (m, 4H), 2.51 (m, 4H), 2.07 (s, 3H). MS (m/z)(M+1)⁺: 484.2.

C36 is arbitrarily assigned the S configuration. ¹H NMR (400 MHz,d6-DMSO) δ 9.80 (s, 1H), 8.81 (s, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.72 (d,J=8.0 Hz, 2H), 7.1-7.5 (m, 5H), 4.09 (s, 1H), 3.96 (t, J=8.8 Hz, 1H),2.7-2.9 (m, 2H), 2.55 (m, 4H), 2.51 (m, 4H), 2.07 (s, 3H). MS (m/z)(M+1)⁺: 484.2.

Example C382-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1-yl)-3-hydroxypropan-1-one

A solution of2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)piperazin-1-yl)-3-hydroxypropan-1-oneC37 (prepared as described for C1, 0.05 mmol), HCHO (0.15 mmol, 30%aqueous) and anhydrous Na₂SO₄ (1.5 mmol) in DCM (2 mL) is stirred at rtfor 30 min. Then NaHB(OAc)₃ (0.3 mmol) is added and the resultingmixture is stirred for 12 h. Purification by prep-HPLC (ACN gradient10-70%) affords2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1-yl)-3-hydroxypropan-1-oneC38. MS (m/z) (M+1)⁺: 552.2.

Type D Compounds

Example D1N1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)piperidine-1,4-dicarboxamide

N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine29a (0.1 mmol), 4-nitrophenyl chloroformate (0.12 mmol) and pyridine(0.24 mmol) in dry DCM (0.5 mL) are stirred at rt for 10 min. Thenpiperidine-4-carboxamide (0.12 mmol) is added and the reaction mixtureis stirred for 2 h. HPLC purification affords the target compound D1 asthe TFA salt. ¹H NMR (400 MHz, d6-DMSO) δ 9.68 (s, 1H), 8.81 (s, 2H),8.05 (s, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.62 (s, 1H), 7.48 (m, 1H), 7.26(m, 4H), 7.08 (d, J=8.4 Hz, 1H), 6.80 (s, 1H), 4.09 (m, 2H), 2.81 (t,J=12.4 Hz, 2H), 2.32 (m, 1H), 2.10 (s, 3H), 1.70 (m, 2H), 1.48 (m, 2H).MS (m/z) (M+1)⁺: 497.2.

Example D2N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methylpiperazine-1-carboxamide

Similar to the preparation of D1. ¹H NMR (400 MHz, d6-DMSO) δ 9.74 (s,1H), 8.80 (s, 2H), 8.37 (s, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.64 (s, 1H),7.49 (d, J=8.4 Hz, 1H), 7.29 (s, 2H), 7.27 (t, J=74.0 Hz, 1H), 7.11 (d,J=8.0 Hz, 1H), 2.86 (s, 3H), 2.51 (m, 4H), 2.54 (m, 4H), 2.11 (s, 3H).MS (m/z) (M+1)⁺: 469.2.

Example D3N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methanesulfonyl-piperazine-1-carboxamide

Similar to the preparation of D1. ¹H NMR (400 MHz, d6-DMSO) δ 9.70 (s,1H), 8.80 (s, 2H), 8.25 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.62 (s, 1H),7.49 (d, J=8.0 Hz, 1H), 7.28 (t, J=74.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H),7.10 (d, J=8.4 Hz, 1H), 3.56 (m, 4H), 3.15 (m, 4H), 2.92 (s, 3H), 2.10(s, 3H). MS (m/z) (M+1)⁺: 533.2.

Example D4N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-acetylpiperazine-1-carboxamide

Similar to the preparation of D1. ¹H NMR (400 MHz, d6-DMSO) δ 9.69 (s,1H), 8.80 (s, 2H), 8.18 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.63 (s, 1H),7.49 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.27 (t, J=74.0 Hz, 1H),7.09 (d, J=8.0 Hz, 1H), 3.56 (m, 4H), 3.35 (m, 4H), 2.10 (s, 3H), 2.04(s, 3H). MS (m/z) (M+1)⁺: 497.2.

Example D7N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)piperazine-1-carboxamide

Similar to the preparation of D1. ¹H NMR (400 MHz, d6-DMSO) δ 9.72 (s,1H), 8.8 (s, 2H), 8.4 (s, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.64 (m, 1H),7.28 (m, 2H), 7.2 (t, J=50 Hz, 1H), 7.1 (m, 2H), 3.8 (t, J=4.9 Hz, 2H),3.24 (t, J=5 Hz, 2H), 2.51 (m, 8H), 2.11 (s, 3H). MS (m/z) (M+1)⁺:499.2.

Example D8N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(phenylmethyl)-4,7-diazaspiro[2.5]octane-7-carboxamideD8a (prepared as described for D1; 0.2 mmol) is dissolved in 10 mL MeOHfollowed by addition of 5% mol of Pd/C (10% in weight). The flask ischarged with a hydrogen balloon for 12 h stiffing. The mixture isfiltered over a celite pad and the filtrate is concentrated to affordN-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamideD8, which is used without further purification. MS (m/z) (M+1)⁺: 523.1.

Example D9N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-4,7-diazaspiro[2.5]octane-7-carboxamide

A solution ofN-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamideD8 (0.05 mmol), HCHO (0.15 mmol, 30% aqueous) and anhydrous Na₂SO₄ (1.5mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)₃ (0.3mmol) is added and the resulting mixture is stirred for 12 h.Purification by prep-HPLC (ACN gradient 10-70%) affordsN-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-4,7-diazaspiro[2.5]octane-7-carboxamideD9. ¹H NMR (400 MHz, d6-DMSO) δ 9.67 (s, 1H), 8.79 (s, 2H), 7.98 (s,1H), 7.76 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.27(d, J=8.4 Hz, 2H), 7.26 (t, J=76.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.78(m, 2H), 2.51 (m, 4H), 2.31 (s, 3H), 2.10 (s, 3H), 0.62 (m, 2H), 0.50(m, 2H). MS (m/z) (M+1)⁺: 537.1.

Example D10N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-4,7-diazaspiro[2,5]octane-7-carboxamide

A solution ofN-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamideD8 (0.05 mmol), 2-hydroxyacetaldehyde (0.6 mmol) and anhydrous Na₂SO₄(1.5 mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)₃(0.3 mmol) is added and the resulting mixture is stirred for 12 h.Purification by prep-HPLC (ACN gradient 10-70%) affordsN-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-4,7-diazaspiro[2.5]octane-7-carboxamideD10. ¹H NMR (400 MHz, d6-DMSO) δ 9.67 (s, 1H), 8.79 (s, 2H), 7.95 (s,1H), 7.76 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.27(d, J=8.4 Hz, 2H), 7.26 (t, J=76.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.89(m, 2H), 2.77 (m, 2H), 2.54 (m, 2H), 2.51 (m, 4H), 2.10 (s, 3H),0.50-0.62 (m, 4H). MS (m/z) (M+1)⁺: 525.2.

Example D11N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide

N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine29a (0.4 mmol), 4-nitrophenyl chloroformate (0.48 mmol) and pyridine(0.8 mmol) in dry DCM (2 mL) are stirred at rt for 10 min. Then ethyl2-(trifluoromethyl)piperazine-1-carboxylate 34b (0.48 mmol) is added andthe reaction mixture is stirred for 2 h. After the reaction is complete,the mixture is diluted with 20 mL of DCM and washed with water. Theorganic layer is separated, dried over Na₂SO₄, filtered and concentratedunder vacuum to afford a residue D11a. To this residue is addeddimethylsulfide (1.2 mmol) and methanesulfonic acid (1.0 mL) and theresulting mixture is stirred at rt for 12 h. HPLC purification (ACNgradient 10-70%) affords D11 as a TFA salt. ¹H NMR (400 MHz, d6-DMSO) δ9.73 (s, 1H), 8.80 (s, 2H), 8.43 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64(s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.28 (t, J=74.0Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.27 (m, 1H), 4.02 (m, 1H), 3.17 (m,1H), 3.0 (s, 1H), 2.51 (m, 4H), 2.11 (s, 3H). MS (m/z) (M+1)⁺: 523.2.

Example D12 N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-(trifluoromethyl)piperazine-1-carboxamide

A solution ofN-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamideD11 (0.05 mmol), HCHO (0.15 mmol, 30% aqueous) and anhydrous Na₂SO₄ (1.5mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)₃ (0.3mmol) is added and the resulting mixture is stirred for 12 h.Purification by prep-HPLC (ACN gradient 10-70%) affordsN-(5-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)-4-methylpiperazine-1-carboxamideD12 as a TFA salt. ¹H NMR (400 MHz, d6-DMSO) δ 9.69 (s, 1H), 8.80 (s,2H), 8.15 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.50 (d, J=8.0Hz, 1H), 7.28 (t, J=74.0 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.4Hz, 1H), 3.68 (m, 1H), 3.54 (m, 1H), 2.88 (m, 1H), 2.51 (m, 4H), 2.47(s, 1H), 2.09 (s, 3H). MS (m/z) (M+1)⁺: 537.2.

Example D13N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-oxopiperazine-1-carboxamide

Similar to the preparation of D1. ¹H NMR (400 MHz, d6-DMSO) δ 9.70 (s,1H), 8.80 (s, 2H), 8.21 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.65 (s, 1H),7.50 (d, J=8.0 Hz, 1H), 7.28 (t, J=74.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H),7.10 (d, J=8.4 Hz, 1H), 4.06 (s, 2H), 2.89 (s, 3H), 2.51 (m, 4H), 2.10(s, 3H). MS (m/z) (M+1)⁺: 483.2.

Type E Compounds

Example E11-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid

To a mixture of 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30 (3.2mmol) and 3-aminophenol (6.42 mmol) in 1,4-dioxane (5 mL) is added p-TSA(5.4 mmol). The reaction mixture is heated at 100° C. for 12 h. Afterthis time, the reaction is diluted with a 2M solution of Na₂CO₃ andextracted with DCM (3×50 mL). The organic layer is washed with brine,dried over Na₂SO₄, and concentrated. Purification by short SiO₂chromatography using a DCM:EtOAc=7:3 as eluant affords(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenol 39. MS (m/z)(M+1)⁺: 330.1.

A solution of 3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenol39 (1.2 mmol), 2-bromoethanol (1.4 mmol) and cesium carbonate (1.6 mmol)in acetonitrile (10 mL) is heated to 85° C. for 12 h then cooled to rt.The reaction is evaporated to dryness then re-dissolved in DCM. Theorganic mixture is washed with water and brine then dried over magnesiumsulfate, filtered and reduced to dryness. Purification by silica gelchromatography with hexane:EtOAc=1:1 as eluant affords2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethanol40a as white solid. MS (m/z) (M+1)⁺: 373.8.

To a solution of2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethanol40 (0.4 mmol) in DCM (15 mL) is added triethyl amine (0.4 mmol) andmethanesulfonyl chloride (0.4 mmol). The reaction mixture is stirred atrt for 12 h then washed with brine and dried over magnesium sulfate,filtered and reduced to dryness. The resulting crude2-(3-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethylmethanesulfonate 40b as tan solid is used without further purification.

2-(3-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethylmethanesulfonate 40b (0.4 mmol), ethyl piperidine-4-carboxylate (0.9mmol) are dissolved in DMF (3 mL) and heated to 95° C. for 6 h thencooled to rt. The reaction mixture is partitioned with EtOAC and water.The organic layer is washed with water, brine, dried over magnesiumsulfate, filtered, and reduced to dryness. The crude product istriturated with MeOH and filtered to yield ethyl1-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate41 as white solid. MS (m/z) (M+1)⁺: 513.2.

To ethyl1-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate41 (78 umol) is added THF (3 mL), MeOH (2 mL) and 3M lithium hydroxide(0.5 mmol). The reaction mixture is stirred at rt for 6 h until completeas detected by LCMS. Subsequently the organic solvents are evaporatedand the reaction mixture is diluted with water (5 mL) and neutralizedwith 3M HCl (0.5 mmol). The resulting precipitate is filtered, washedwith water and air dried to yield1-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid E1 as white solid. ¹H NMR (400 MHz, d6-DMSO) δ 12.12 (s, 1H), 9.79(s, 1H), 8.85 (s, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.52 (bs, 1H), 7.34 (bd,J=8.0 Hz, 1H), 7.31 (t, J=74.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.18 (t,J=8.0 Hz, 1H), 6.56 (bd, J=8.0 Hz, 1H) 4.05 (m, 2H), 2.88 (m, 2H), 2.67(m, 2H), 2.20 (m, 1H), 2.09 (m, 2H), 1.78 (m, 2H), 1.57 (m, 2H). MS(m/z) (M+1)⁺: 484.2.

Example E21-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid

A solution of 2-(3-aminophenyl)ethanol (1.8 mmol),2-chloro-5-(4-difluoromethoxy-phenyl)-pyrimidine 30 (1.8 mmol) and p-TSA(1.8 mmol) in dioxane (10 mL) is heated at 100° C. for 12 h then cooledto rt. The reaction mixture is slowly added to water (100 mL) withstirring. The resulting precipitate is collected by filtration, washedwith water and air dried. The crude precipitate of2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)ethanol42a is used without further purification. MS (m/z) (M+1)⁺: 357.9.

To a solution of2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)ethanol42a (0.7 mmol) in DCM (20 mL) is added triethyl amine (0.8 mmol) andmethanesulfonyl chloride (0.8 mmol). The reaction mixture is stirred atrt for 12 h then washed with brine and dried over magnesium sulfate,filtered, and reduced to dryness. The resulting3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethylmethanesulfonate 42b as crude tan solid, is used without furtherpurification.

3-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethylmethanesulfonate 42b (0.7 mmol) and ethyl piperidine-4-carboxylate (1.7mmol) are dissolved in DMF (6 mL) and heated to 95° C. for 6 h thencooled to rt. The reaction mixture is partitioned with EtOAc and water.The organic layer is washed with water, brine, dried over magnesiumsulfate, filtered and reduced to dryness. The crude material is purifiedby column chromatography on silica with hexane:EtOAc=1:1 to 100% EtOAcas eluant to yield ethyl1-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate43 as clear crystalline solid. MS (m/z) (M+1)⁺: 497.2.

To ethyl1-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate43 (0.3 mmol) is added THF (3 mL), MeOH (2 mL) and 3.0M lithiumhydroxide (1.8 mmol). The reaction mixture is stirred at rt for 6 huntil complete as detected by LCMS. Subsequently the organic solventsare evaporated and the reaction mixture is diluted with water (10 mL)then neutralized with 3M HCl (1.8 mmol). The resulting precipitate isfiltered, washed with water and air dried to yield E2 as white solid. ¹HNMR (400 MHz, d6-DMSO) δ 9.75 (s, 1H), 8.83 (s, 2H), 7.78 (d, J=8.0 Hz,2H), 7.65 (m, 2H), 7.31 (t, J=74.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.21(t, J=8.0 Hz, 1H), 6.83 (d, J=7.2 Hz, 1H), 2.71 (m, 2H), 2.21 (m, 1H),2.03 (m, 2H), 1.81 (m, 2H), 1.58 (m, 2H). MS (m/z) (M+1)⁺: 468.2.

Example E31-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylicacid

To a mixture of 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30(0.40 mmol) and (3-aminophenyl)methanol (0.40 mmol) in 1,4-dioxane (0.5mL) is added p-TSA (0.4 mmol). The reaction mixture is heated at 105° C.for 2 days. After this time, the reaction mixture is diluted with asolution of 2M Na₂CO₃ (30 mL) and extracted with DCM (3×30 mL). Theorganic layer is washed with brine, dried over Na₂SO₄ and concentrated.Purification by short silica gel chromatography using a hexane:EtOAc=1:2affords(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)methanol 36.¹H NMR (400 MHz, d4-MeOH) δ 8.56 (s, 2H), 7.65 (m, 1H), 7.48-7.52 (m,1H), 7.42-7.46 (m, 2H), 7.29 (t, J=8 Hz, 1H), 7.15-7.18 (m, 3H),6.99-7.03 (m, 1H), 6.49 (t, J=73.6 Hz, 1H), 4.67 (s, 2H). MS (m/z)(M+1)⁺ 344.1.

To a solution of(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)methanol 36(6.22 mmol) in DCM (30 mL) is added triethylamine (9.33 mmol) andmethanesulfonyl chloride (7.47 mmol). The reaction mixture is stirred atrt for 1.5 h. The reaction is diluted with H₂O (10 mL) and washed withNa₂CO₃ solution (3×20 mL). The organic layer is washed with brine, driedover MgSO₄ and concentrated to afford3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzylmethanesulfonate 37. MS (m/z) (M+1)⁺422.1.

To a solution of3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzylmethanesulfonate 37 (0.050 mmol) in anhydrous DMF (1 mL) is added methylpiperidine-4-carboxylate (0.10 mmol) and the solution is heated at 100°C. for 8 h. After the reaction is complete, the mixture is diluted withTHF:MeOH:H₂O (3:2:1, 5 mL). To the reaction mixture is added 6N LiOH(0.30 mmol). The reaction is stirred at rt for 1 h. Purification bypreparative LC/MS affords 1-(3-(5(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylicacid E3. ¹H NMR (400 MHz, d4-MeOH) δ 8.64 (s, 2H), 7.78 (d, J=8.8 Hz,2H), 7.56 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz,2H), 6.78 (t, J=74.0 Hz, 1H), 4.11 (s, 2H), 3.31 (m, 2H), 2.92 (m, 2H),2.36 (m, 1H), 2.02 (m, 2H), 1.81 (m, 2H). MS (m/z) (M+1)⁺: 455.2.

Type F Compounds

Example F11-(2-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylicacid

To a mixture of -5-bromo 2-chloropyrimidine 4 (1.1 mmol) and4-fluoro-3-methoxyaniline (1.1 mmol) in 5 mL of 1,4-dioxane is addedp-TSA (1.0 mmol). The reaction mixture is heated at 105° C. for 4 h.After this time, the reaction mixture is diluted with a 2M Na₂CO₃solution and extracted with DCM (3×50 mL). The organic layer is washedwith brine, dried over Na₂SO₄ and concentrated. Purification prep HPLC(ACN gradient 20-70%)5-bromo-N-(4-fluoro-3-methoxyphenyl)pyrimidin-2-amine 44 as brown solid.MS (m/z) (M+1)⁺: 299.1.

To a solution of 5-bromo-N-(4-fluoro-3-methoxyphenyl)pyrimidin-2-amine44 (0.25 mmol) in 3 mL of anhydrous DCM at 0° C. is added BBr₃ (1.27mmol) drop wise. The reaction mixture is stirred at rt for 12 h. Afterthis time the reaction mixture is diluted with a 2M solution of Na₂CO₃and extracted with DCM (2×20 mL). The organic layer is washed withbrine, dried over Na₂SO₄ and concentrated to afford5-(5-bromopyrimidin-2-ylamino)-2-fluorophenol 45 as brownish solid whichis used without further purification. MS (m/z) (M+1)⁺: 286.2.

A solution of 5-(5-bromopyrimidin-2-ylamino)-2-fluorophenol 45 (0.25mmol), 2-bromoethanol (0.28 mmol) and cesium carbonate (0.36 mmol) inacetonitrile (3 mL) is heated to 100° C. for 12 h. The reaction isevaporated to dryness then re-dissolved in DCM. The organic mixture iswashed with water and brine then dried over magnesium sulfate, filteredand reduced to dryness to yield2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethanol 46a as a brownsolid which is used without further purification. MS (m/z) (M+1)⁺:329.2.

To a solution of2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethanol 46a (0.24mmol) in DCM (15 mL) is added triethylamine (0.24 mmol) andmethanesulfonyl chloride (0.24 mmol). The reaction mixture is stirred atrt for 12 h then washed with brine and dried over magnesium sulfate,filtered and reduced to dryness. The resulting tan solid of2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl methanesulfonate46b is used without further purification. MS (m/z) (M+1)⁺: 407.1.

2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl methanesulfonate46b (0.24 mmol) and methyl piperidine-4-carboxylate (0.48 mmol) aredissolved in NMP (2 mL) and heated to 90° C. for 3 h. The reactionmixture is cooled to rt and diluted with water and extracted with EtOAc(2×30 mL). The organic layer is washed with water, brine, dried oversodium sulfate, and concentrated to dryness. The crude product ispurified by short SiO₂ chromatography using DCM:hexane=9:1 as eluant toyield methyl1-(2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate47 as light brown solid. MS (m/z) (M+1)⁺: 454.1.

To a solution of methyl1-(2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate47 (0.24 mmol) in 1,4-dioxane (2.0 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(0.28 mmol), 1.8M K₂CO₃ (0.5 mmol) and Pd(PPh₃)₄ (0.017 mmol). Thereaction is evacuated and backfilled with nitrogen twice then heated at90° C. for 12 h. The reaction mixture is cooled to rt, diluted withwater (10 mL) and extracted with DCM (2×20 mL). The organic layer isseparated, dried over Na₂SO₄ and concentrated. Purification bypreparative HPLC (ACN gradient 20-70%) affords methyl1-(2-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate48 as white solid. MS (m/z) (M+1)⁺: 517.1.

To methyl1-(2-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate48 (0.072 mmol) is added THF (1 mL), MeOH (0.8 mL) and 6M lithiumhydroxide (0.42 mmol). The reaction mixture is stirred at rt for 6 huntil complete by LCMS. The organic solvents are evaporated and thereaction mixture is diluted with water and neutralized with 6M HCl (0.42mmol). The resulting precipitate is filtered, washed with water and airdried to yield F1 as white solid. ¹H NMR (400 MHz, d6-DMSO) δ 9.88 (s,1H), 8.85 (s, 2H), 7.79 (m, 2H), 7.71 (dd, J=8.0, 12.0 Hz, 1H), 7.46 (m,1H), 7.31 (m, 2H), 7.29 (t, J=69.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.20(d, J=8.0 Hz, 1H), 4.41 (m, 2H), 3.58 (m, 6H), 3.14 (m, 2H), 2.12 (m,2H), 1.77 (m, 1H). MS (m/z) (M+1)⁺: 503.2.

Example F21-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylicacid

To a solution of (5-amino-2-methyl-phenyl)-acetic acid methyl ester 49(1.4 mmol) in THF (7 mL) at 0° C. is added 1M lithium aluminum hydrideTHF solution (1.4 mmol). The reaction is stirred at rt for 6 h andsubsequently quenched with ice water and partitioned with ethyl acetate.The organic layer is washed with brine, dried over magnesium sulfate,filtered and reduced to dryness to yield2-(5-amino-2-methylphenyl)ethanol 50 as tan crystalline solid, which isused without further purification.

A solution of 2-chloro-5-(4-difluoromethoxy-phenyl)-pyrimidine 30 (1.3mmol), 2-(5-Amino-2-methyl-phenyl)-ethanol 50 (1.3 mmol) and p-TSA (0.24g, 1.3 mmol) in dioxane (10 mL) is heated at 100° C. for 12 h thencooled to rt. The reaction mixture is slowly added to water (100 mL)with stirring. The resulting precipitate is collected by filtration,washed with water and air dried. The crude precipitate is purified bycolumn chromatography on silica with hexanes:EtOAc=1:1 as eluant toyield2-{5-[5-(4-difluoromethoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-phenyl}-ethanol51a as solid. MS (m/z) (M+1)⁺: 372.3.

To a solution of2-{5-[5-(4-difluoromethoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-phenyl}-ethanol51a (0.8 mmol) in DCM (25 mL) is added triethyl amine (1.0 mmol) andmethanesulfonyl chloride (0.9 mmol). The reaction mixture is stirred atrt for 12 h then washed with brine and dried over magnesium sulfate,filtered and reduced to dryness. The resulting5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethylmethanesulfonate 51b as clear amber oil is used without furtherpurification. MS (m/z) (M+1)⁺: 450.1.

5-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethylmethanesulfonate 51b (0.9 mmol), ethyl piperidine-4-carboxylate (2.2mmol) are dissolved in DMF (10 mL) and heated to 90° C. for 4 h thencooled to rt. The reaction mixture is partitioned with EtOAc and water.The organic layer is washed with water, brine, dried over magnesiumsulfate, filtered and reduced to dryness. The crude material is purifiedby column chromatography on silica with hexane:EtOAc=1:1 to 100% EtOAcas eluant to yield ethyl1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylate52 as clear viscous oil. MS (m/z) (M+1)⁺: 511.2.

To ethyl1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylate52 (0.6 mmol) is added THF (3 mL), MeOH (2 mL) and 3M lithium hydroxide(7.3 mmol). The reaction mixture is stirred at rt for 6 h until completeas detected by LCMS. Subsequently, the organic solvents are evaporatedand the reaction mixture is diluted with water (10 mL) then neutralizedwith 3M HCl (7.3 mmol). The resulting precipitate is filtered, washedwith water and air dried. The crude precipitate is purified bypreparative LCMS to yield1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylicacid F2 as white solid. ¹H NMR (400 MHz, d6-DMSO) δ 9.69 (s, 1H), 8.79(s, 2H), 7.75 (d, J=8.0 Hz, 2H), 7.60 (bd, J=8.0 Hz, 1H), 7.56 (bs, 1H),7.46 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 3.19 (m,1H), 2.96 (m, 2H), 2.27 (s, 3H), 2.10 (m, 2H), 1.75 (m, 2H). MS (m/z)(M+1)⁺: 483.2.

Type G Compounds

Example G1 4-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-methylpiperazin-2-one

To a solution of 4-(5-bromopyrimidin-2-ylamino)benzaldehyde 16 (1.26mmol) in acetone (5 mL) is added Jones' reagent (3.0 mmol of a 4Msolution) portionwise until complete conversion as detected by LCMS.Isopropanol (10 mL) is added and the reaction mixture is stirred at rtfor 1 h, then the solvent is removed under vacuum. The green residue isre-dissolved in water and partitioned with ethyl acetate. The organiclayer is washed with water, brine, dried over sodium sulfate, filteredand reduced to dryness to afford 4-(5-bromopyrimidin-2-ylamino)benzoicacid 53 as yellow solid which is used without further purification. MS(m/z) (M+1)⁺: 295.1.

To 4-(5-bromopyrimidin-2-ylamino)benzoic acid 53 (0.25 mmol) in1,4-dioxane (2.0 mL) is added2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7(0.28 mmol), 1.8M K₂CO₃ (0.5 mmol) and Pd(PPh₃)₄ (0.017 mmol). Thereaction is evacuated and backfilled with nitrogen twice then heated at90° C. for 8 h. The reaction mixture is diluted with water (10 mL)neutralized with 2M HCl and extracted with DCM (3×20 mL). Purificationby preparative HPLC (ACN gradient 20-70%) affords4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoic acid 54 aswhite solid. MS (m/z) (M+1)⁺: 358.2.

4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoic acid 54(0.022 mmol), HATU (0.027 mmol) and 1-methylpiperazin-2-one (0.022 mmol)are dissolved in dry DMF (0.5 mL) at rt. Diisopropylethylamine (0.06mmol) is added to the solution. The reaction mixture is stirred for 1 hat rt. HPLC purification affords4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-methylpiperazin-2-oneG1 as a TFA salt. ¹H NMR (400 MHz, d6-DMSO) δ 10.1 (s, 1H), 8.87 (s,2H), 7.90 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.4 Hz,2H), 7.29 (d, J=8.0 Hz, 2H), 7.12 (t, J=51.2 Hz, 1H), 4.1 (s, 2H), 2.87(s, 3H), 2.55 (m, 4H). MS (m/z) (M+1)⁺: 454.2.

Example G24-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-(2-hydroxyethyl)piperazin-2-one

Similar to the preparation of G1. ¹H NMR (400 MHz, d6-DMSO) δ 10.1 (s,1H), 8.87 (s, 2H), 7.90 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.44(d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.2 (t, J=50.2 Hz, 1H), 4.1(s, 2H), 2.55 (m, 6H), 2.51 (m, 4H). MS (m/z) (M+1)⁺: 484.1.

Example G34-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)piperazin-2-one

Similar to the preparation of G1. ¹H NMR (400 MHz, d6-DMSO) δ 10.12 (s,1H), 8.89 (s, 2H), 8.14 (bs, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.31 (t, J=72.0 Hz, 1H), 7.29 (d, J=8.0Hz, 2H), 4.01 (s, 2H), 3.65 (m, 2H), 3.28 (m, 4H). MS (m/z) (M+1)⁺:440.2.

Example G4(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)(3-(trifluoromethyl)piperazin-1-yl)methanone

Similar to the preparation of G1. ¹H NMR (400 MHz, d6-DMSO) δ 10.13 (s,1H), 8.89 (s, 2H), 7.93 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.44(d, J=8.0 Hz, 2H), 7.31 (t, J=76.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 4.01(bs, 4H), 3.30 (bs, 2H), 3.28 (bs, 2H). MS (m/z) (M+1)⁺: 494.2.

Table 1 describes representative compounds of the invention, preparedfollowing the procedures described above. Compounds in Table 1 have anactivity of <1 μM in c-kit Mo7e assay and/or PDGFR TG-HA-VSMC assay.

TABLE 1 Example No. Structure MS [M + 1]⁺ A1

447.2 A2

429.2 A3

485.2 A4

455.2 A5

473.2 A6

469.2 B1

468.2 B2

452.2 B3

454.2 B4

454.2 B5

468.2 B6

466.1 B7

437.2 B8

472.2 B9

494.1 B10

496.2 C1

447.2 C2

485.2 C3

485.1 C4

485.1 C5

459.1 C6

459.1 C7

459.1 C8

459.1 C9

459.2 C10

499.2 C11

499.1 C12

499.2 C13

499.1 C14

499.2 C15

499.2 C16

485 .2 C17

485.2 C18

485.1 C19

485.1 C20

485.2 C21

485.1 C22

485.2 C23

485.2 C24

485.1 C25

485.2 C26

485.2 C27

485.1 C28

485.1 C29

485.2 C30

485.1 C31

485.2 C32

467.2 C33

455.1 C34

484.4 C35

484.1 C36

484.2 C37

538.1 C38

552.1 D1

497.2 D2

469.2 D3

533.2 D4

497.2 D5

480.2 D6

456.2 D7

499.2 D8

481.2 D9

495.2 D10

524.56 D11

522.47 D12

536.50 D13

483.2 D14

513.1 E1

485.2 E2

469.2 E3

455.1 F1

503.2 F2

483.2 G1

454.2 G2

485.2 G3

439.4 G4

495.1

Assays

Compounds of the present invention are assayed to measure their capacityto selectively inhibit the proliferation of wild type Ba/F3 cells andBa/F3 cells transformed with Tel c-kit kinase and Tel PDGFR fusedtyrosine kinases. In addition, compounds of the invention mayselectively inhibit SCF dependent proliferation in Mo7e cells. Further,compounds are assayed to measure their capacity to inhibit Abl, ARG,BCR-Abl, BRK, EphB, Fms, Fyn, KDR, c-Kit, LCK, PDGF-R, b-Raf, c-Raf,SAPK2, Src, Tie2 and TrkB kinases.

Proliferation Assay: BaF3 Library—Bright glo Readout Protocol

Compounds are tested for their ability to inhibit the proliferation ofwt Ba/F3 cells and Ba/F3 cells transformed with Tel fused tyrosinekinases. Untransformed Ba/F3 cells are maintained in media containingrecombinant IL3. Cells are plated into 384 well TC plates at 5,000 cellsin 50 ul media per well and test compound at 0.06 nM to 10 μM is added.The cells are then incubated for 48 hours at 37° C., 5% CO₂. Afterincubating the cells, 25 μL of BRIGHT GLO® (Promega) is added to eachwell following manufacturer's instructions and the plates are read usingAnalyst GT—Luminescence mode—50000 integration time in RLU. IC₅₀ valuesare determined from a dose response curve.

Mo7e Assay

The compounds described herein are tested for inhibition of SCFdependent proliferation using Mo7e cells which endogenously expressc-kit in a 96 well format. Two-fold serially diluted test compounds(Cmax=10 μM) are evaluated for their antiproliferative activity of Mo7ecells stimulated with human recombinant SCF. After 48 hours ofincubation at 37° C., cell viability is measured by using a MTTcolorimetric assay from Promega.

c-Kit HTRF Protocol

An aliquot (5 μL) of a 2× concentration of c-kit enzyme mix 25 ng c-kit(5 ng/μL) and 2 μM of Biotin-EEEPQYEEIPIYLELLP-NH₂ peptide in kinasebuffer (20 mM Tris pH 7.5, 10 mM MgCl₂, 0.01% BSA, 0.1% Brij35, 1 mMDTT, 5% glycerol, 0.05 mM Na₃VO₄) is added to each well of a 384proxiplate (Packard). Each well of the last row of the proxiplate has 5μL of c-kit enzyme mix without c-kit to ascertain the background level.Compounds of the invention are added to each well and the plates areincubated for 30 minutes at room temperature. 2×ATP (40 μM) in kinasebuffer (5 μL) is added to each well and the plate is incubated at roomtemperature form 3 hours. Detection mix (50% KF, 40% kinase buffer, 10%EDTA, 1:100 diluted Mab PT66-K (cat# 61T66KLB) and 1:100 dilutedStreptavidin-XL (cat#611SAXLB)0 (10 μL) is added to each well and theplates are further incubated for 1 to 2 hours at room temperature. TheHTRF signal is then read on a detector.

Human TG-HA-VSMC Proliferation Assay

Human TG-HA-VSMC cells (ATCC) are grown in DMEM supplemented with 10%FBS to 80-90% confluence prior to resuspending in DMEM supplemented with1% FBS and 30 ng/mL recombinant human PDGF-BB at 6e4 cells/mL. Cells arethen aliquoted into 384 well plates at 50 uL/well, incubated for 20 h at37° C., then treated with 0.5 μL of 100× compounds for 48 h at 37° C.After the treatment, 25 μL of CellTiter-Glo is added to each well for 15min, then the plates are read on the CLIPR (Molecular Devices).

PDGFRα/β Lance Assay Protocol

An aliquot (2.5 μL) of a 2× concentration of PDGFRβ peptide and ATP mix(4 μM biotin-βA-βA-βA-AEEEEYVFIEAKKK peptide, 20 μM ATP in assay buffer(20 mM Hepes, 54 mM MgCl₂, 0.01% BSA, 0.05% Tween-20, 1 mM DTT, 10%glycerol, 50 μM Na₃VO₄)) is added to each well of a 384 proxiplate(Packard). The plates are centrifuged and compounds of the invention (50nL) are added to each well via a pintool dispenser. To each well isadded (2.5 μL) of a 2× concentration of enzyme mix (PDGFRα at 4.5 ng/μL(cat# PV4117) or PDGFRβ at 1.5 ng/μL (cat# PV3591) in assay buffer) orassay buffer alone without PDGFRα/β enzyme. The plates are incubated for1.5 hours at room temperature. Detection mix (5 μL; 50% 1M KF, 40%kinase buffer, 10% EDTA, 1:100 diluted Mab PT66-K (cat# 61T66KLB) and1:100 diluted Streptavidin-XL (cat# 611SAXLB) is added to each well andthe proxiplate is incubated for 1 hour at room temperature beforereading the HTRF signal on a detector.

Ba/F3 FL FLT3 Proliferation Assay

The murine cell line used is the Ba/F3 murine pro-B cell line that overexpresses full length FLT3 construct. These cells are maintained in RPMI1640/10% fetal bovine serum (RPMI/FBS) supplemented with penicillin 50μg/mL, streptomycin 50 μg/mL and L-glutamine 200 mM with the addition ofmurine recombinant IL3. Ba/F3 full length FLT3 cells undergo IL3starvation for 16 hours and then plated into 384 well TC plates at 5,000cells in 25 uL media per well and test compound at 0.06 nM to 10 μM isadded. After the compound addition FLT3 ligand or IL3 for cytotoxicitycontrol are added in 25 ul media per well at the appropriateconcentrations. The cells are then incubated for 48 hours at 37° C., 5%CO₂. After incubating the cells, 25 μL of BRIGHT GLO® (Promega) is addedto each well following manufacturer's instructions and the plates areread using Analyst GT—Luminescence mode—50000 integration time in RLU.

Inhibition of Cellular BCR-Abl Dependent Proliferation (High ThroughputMethod)

The murine cell line used is the 32D hemopoietic progenitor cell linetransformed with BCR-Abl cDNA (32D-p210). These cells are maintained inRPMI/10% fetal calf serum (RPMI/FCS) supplemented with penicillin 50μg/mL, streptomycin 50 μg/mL and L-glutamine 200 mM. Untransformed 32Dcells are similarly maintained with the addition of 15% of WEHIconditioned medium as a source of IL3.

50 μL of a 32D or 32D-p210 cells suspension are plated in Greiner 384well microplates (black) at a density of 5000 cells per well. 50 nL oftest compound (1 mM in DMSO stock solution) is added to each well(STI571 is included as a positive control). The cells are incubated for72 hours at 37° C., 5% CO₂. 10 μL of a 60% Alamar Blue solution (Tekdiagnostics) is added to each well and the cells are incubated for anadditional 24 hours. The fluorescence intensity (Excitation at 530 nm,Emission at 580 nm) is quantified using the Acquest™ system (MolecularDevices).

Inhibition of Cellular BCR-Abl Dependent Proliferation

32D-p210 cells are plated into 96 well TC plates at a density of 15,000cells per well. 50 μL of two fold serial dilutions of the test compound(C_(max) is 40 μM) are added to each well (STI571 is included as apositive control). After incubating the cells for 48 hours at 37° C., 5%CO₂, 15 μL of MTT (Promega) is added to each well and the cells areincubated for an additional 5 hours. The optical density at 570 nm isquantified spectrophotometrically and IC₅₀ values are determined from adose response curve.

Effect on Cell Cycle Distribution

32D and 32D-p210 cells are plated into 6 well TC plates at 2.5×10⁶ cellsper well in 5 mL of medium and a test compound at 1 or 10 μM is added(STI571 is included as a control). The cells are then incubated for 24or 48 hours at 37° C., 5% CO₂. 2 mL of cell suspension is washed withPBS, fixed in 70% EtOH for 1 hour and treated with PBS/EDTA/RNase A for30 minutes. Propidium iodide (Cf=10 μg/ml) is added and the fluorescenceintensity is quantified by flow cytometry on the FACScalibur™ system (BDBiosciences). Test compounds of the present invention demonstrate anapoptotic effect on the 32D-p210 cells but do not induce apoptosis inthe 32D parental cells.

Effect on Cellular BCR-Abl Autophosphorylation

BCR-Abl autophosphorylation is quantified with capture ELISA using ac-abl specific capture antibody and an antiphosphotyrosine antibody.32D-p210 cells are plated in 96 well TC plates at 2×10⁵ cells per wellin 50 μL of medium. 50 μL of two fold serial dilutions of test compounds(C_(max) is 10 μM) are added to each well (STI571 is included as apositive control). The cells are incubated for 90 minutes at 37° C., 5%CO₂. The cells are then treated for 1 hour on ice with 150 μL of lysisbuffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA and 1%NP-40) containing protease and phosphatase inhibitors. 50 μL of celllysate is added to 96 well optiplates previously coated with anti-ablspecific antibody and blocked. The plates are incubated for 4 hours at4° C. After washing with TBS-Tween 20 buffer, 50 μL ofalkaline-phosphatase conjugated anti-phosphotyrosine antibody is addedand the plate is further incubated overnight at 4° C. After washing withTBS-Tween 20 buffer, 90 μL of a luminescent substrate are added and theluminescence is quantified using the Acquest™ system (MolecularDevices). Test compounds of the invention that inhibit the proliferationof the BCR-Abl expressing cells, inhibit the cellular BCR-Ablautophosphorylation in a dose-dependent manner.

Effect on Proliferation of Cells Expressing Mutant Forms of Bcr-abl

Compounds of the invention are tested for their antiproliferative effecton Ba/F3 cells expressing either wild type or the mutant forms ofBCR-Abl (G250E, E255V, T315I, F317L, M351T) that confers resistance ordiminished sensitivity to STI571. The antiproliferative effect of thesecompounds on the mutant-BCR-Abl expressing cells and on the nontransformed cells are tested at 10, 3.3, 1.1 and 0.37 μM as describedabove (in media lacking IL3). The IC₅₀ values of the compounds lackingtoxicity on the untransformed cells are determined from the doseresponse curves obtained as describe above.

FGFR3 (Enzymatic Assay)

Kinase activity assay with purified FGFR3 (Upstate) is carried out in afinal volume of 10 μL containing 0.25 μg/mL of enzyme in kinase buffer(30 mM Tris-HCl pH 7.5, 15 mM MgCl₂, 4.5 mM MnCl₂, 15 μM Na₃VO₄ and 50μg/mL BSA), and substrates (5 μg/mL biotin-poly-EY(Glu, Tyr) (CIS-US,Inc.) and 3 μM ATP). Two solutions are made: the first solution of 5 μLcontaining the FGFR3 enzyme in kinase buffer is first dispensed into384-format ProxiPlate® (Perkin-Elmer) followed by adding 50 nL ofcompounds dissolved in DMSO. A 5 μL of second solution containing thesubstrate (poly-EY) and ATP in kinase buffer is then added to eachwells. The reactions are incubated at room temperature for one hour,stopped by adding 10 μL of HTRF detection mixture, which contains 30 mMTris-HCl pH7.5, 0.5 M KF, 50 mM ETDA, 0.2 mg/mL BSA, 15 μg/mLstreptavidin-XL665 (CIS-US, Inc.) and 150 ng/mL cryptate conjugatedanti-phosphotyrosine antibody (CIS-US, Inc.). After one hour of roomtemperature incubation to allow for streptavidin-biotin interaction,time resolved florescent signals are read on Analyst GT (MolecularDevices Corp.). IC₅₀ values are calculated by linear regression analysisof the percentage inhibition of each compound at 12 concentrations (1:3dilution from 50 μM to 0.28 nM). In this assay, compounds of theinvention have an IC₅₀ in the range of 10 nM to 2 μM.

FGFR3 (Cellular Assay)

Compounds of the invention are tested for their ability to inhibittransformed Ba/F3-TEL-FGFR3 cells proliferation, which is depended onFGFR3 cellular kinase activity. Ba/F3-TEL-FGFR3 are cultured up to800,000 cells/mL in suspension, with RPMI 1640 supplemented with 10%fetal bovine serum as the culture medium. Cells are dispensed into384-well format plate at 5000 cell/well in 50 μL culture medium.Compounds of the invention are dissolved and diluted in dimethylsufoxide(DMSO). Twelve points 1:3 serial dilutions are made into DMSO to createconcentrations gradient ranging typically from 10 mM to 0.05 μM. Cellsare added with 50 nL of diluted compounds and incubated for 48 hours incell culture incubator. AlamarBlue® (TREK Diagnostic Systems), which canbe used to monitor the reducing environment created by proliferatingcells, are added to cells at final concentration of 10%. After anadditional four hours of incubation in a 37° C. cell culture incubator,fluorescence signals from reduced AlamarBlue® (Excitation at 530 nm,Emission at 580 nm) are quantified on Analyst GT (Molecular DevicesCorp.). IC₅₀ values are calculated by linear regression analysis of thepercentage inhibition of each compound at 12 concentrations.

b-Raf—Enzymatic Assay

Compounds of the invention are tested for their ability to inhibit theactivity of b-Raf. The assay is carried out in 384-well MaxiSorp plates(NUNC) with black walls and clear bottom. The substrate, IκBα is dilutedin DPBS (1:750) and 15 μL is added to each well. The plates areincubated at 4° C. overnight and washed 3 times with TBST (25 mM Tris,pH 8.0, 150 mM NaCl and 0.05% Tween-20) using the EMBLA plate washer.Plates are blocked by Superblock (15 μL/well) for 3 hours at roomtemperature, washed 3 times with TBST and pat-dried. Assay buffercontaining 20 μM ATP (10A) is added to each well followed by 100 nL or500 nL of compound. B-Raf is diluted in the assay buffer (1 μL into 25μL) and 10 μL of diluted b-Raf is added to each well (0.4 μg/well). Theplates are incubated at room temperature for 2.5 hours. The kinasereaction is stopped by washing the plates 6 times with TBST. Phosph-IκBα(Ser32/36) antibody is diluted in Superblock (1:10,000) and 15 μL isadded to each well. The plates are incubated at 4° C. overnight andwashed 6 times with TBST. AP-conjugated goat-anti-mouse IgG is dilutedin Superblock (1:1,500) and 15 μL is added to each well. Plates areincubated at room temperature for 1 hour and washed 6 times with TBST.15 μL of fluorescent Attophos AP substrate (Promega) is added to eachwell and plates are incubated at room temperature for 15 minutes. Platesare read on Acquest or Analyst GT using a Fluorescence Intensity Program(Excitation 455 nm, Emission 580 nm).

b-Raf—Cellular Assay

Compounds of the invention are tested in A375 cells for their ability toinhibit phosphorylation of MEK. A375 cell line (ATCC) is derived from ahuman melanoma patient and it has a V599E mutation on the B-Raf gene.The levels of phosphorylated MEK are elevated due to the mutation ofB-Raf. Sub-confluent to confluent A375 cells are incubated withcompounds for 2 hours at 37° C. in serum free medium. Cells are thenwashed once with cold PBS and lysed with the lysis buffer containing 1%Triton X100. After centrifugation, the supernatants are subjected toSDS-PAGE, and then transferred to nitrocellulose membranes. Themembranes are then subjected to western blotting with anti-phospho-MEKantibody (ser217/221) (Cell Signaling). The amount of phosphorylated MEKis monitored by the density of phospho-MEK bands on the nitrocellulosemembranes.

Upstate KinaseProfiler™—Radio-Enzymatic Filter Binding Assay

Compounds of the invention are assessed for their ability to inhibitindividual members of the kinase panel. The compounds are tested induplicates at a final concentration of 10 μM following this genericprotocol. Kinase buffer (2.5 μL, 10×—containing MnCl₂ when required),active kinase (0.001-0.01 Units; 2.5 μL), specific or Poly(Glu-4-Tyr)peptide (5-500 μM or 0.01 mg/ml) in kinase buffer and kinase buffer (50μM; 5 μL) are mixed in an eppendorf on ice. A Mg/ATP mix (10 μL; 67.5(or 33.75) mM MgCl₂, 450 (or 225) μM ATP and 1 μCi/μl [γ-³²P]-ATP(3000Ci/mmol)) is added and the reaction is incubated at about 30° C.for about 10 minutes. The reaction mixture is spotted (20 μL) onto a 2cm×2 cm P81 (phosphocellulose, for positively charged peptidesubstrates) or Whatman No. 1 (for Poly (Glu-4-Tyr) peptide substrate)paper square. The assay squares are washed 4 times, for 5 minutes each,with 0.75% phosphoric acid and washed once with acetone for 5 minutes.The assay squares are transferred to a scintillation vial, 5 mlscintillation cocktail are added and ³²P incorporation (cpm) to thepeptide substrate is quantified with a Beckman scintillation counter.Percentage inhibition is calculated for each reaction.

*****

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof; wherein: R¹ is ahaloalkyl having 1-6 fluorine atoms; R² is C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl, each of which may be optionally substituted with halo,amino or hydroxyl groups; halo, cyano, nitro, (CR₂)_(k)OR⁷,(CR₂)_(k)O(CR₂)₁₋₄R⁷, (CR₂)_(k)SR⁷, (CR₂)_(k)NR⁹R¹⁰,(CR₂)_(k)C(O)O₀₋₁R⁷, OC(O)R⁷, (CR₂)_(k)C(S)R⁷, (CR₂)_(k)C(O)NR⁹R¹⁰,(CR₂)_(k)C(O)NR(CR₂)₀₋₆C(O)O₀₋₁R⁷, (CR₂)_(k)NRC(O)O₀₋₁R⁷,(CR₂)_(k)S(O)₁₋₂NR⁹R¹⁰, (CR₂)_(k)S(O)₁₋₂R⁸, (CR₂)_(k)NRS(O)₁₋₂R⁸ or(CR₂)_(k)R⁶; or any two adjacent R² groups together may form anoptionally substituted 5-8 membered carbocyclic, heterocyclic, aryl orheteroaryl ring; R³ is selected from the group consisting of

R⁹ and R¹⁰ are independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, each of which may be optionally substituted with halo, amino,hydroxyl, alkoxy, cyano, carboxyl or R⁶; (CR₂)_(k)CN, (CR₂)₁₋₆NR⁷R⁷,(CR₂)₁₋₆OR⁷, (CR₂)_(k)C(O)O₀₋₁R⁷, (CR₂)_(k)C(O)NR⁷R⁷ or (CR₂)_(k)—R⁶; R⁶is an optionally substituted C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, or a 5-10membered heteroaryl or 5-7 membered heterocyclic ring; R⁷ and R⁸ areindependently (CR₂)_(k—)R⁶ or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl,each of which may be optionally substituted with halo, amino, amido, orhydroxyl, alkoxy, cyano, carboxyl or R⁶; or R⁷ is H; each R is H orC₁₋₆alkyl; each k is 0-6; and j and m are independently 0-4.
 2. Thecompound of claim 1, wherein R¹ is —CHF₂, —CF₃, —CH₂CF₃, —CF₂CH₃, or—CH₂CF₃.
 3. The compound of claim 2, wherein R¹ is —CHF₂.
 4. Thecompound of claim 1, wherein R² if present, is halo, C₁₋₆ alkyl, C₁₋₆alkoxy, hydroxy or CO₂R⁷ and R⁷ is H or C₁₋₆ alkyl.
 5. The compound ofclaim 1, wherein said compound is selected from the group consisting of:N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-methylpiperidine-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;(1S,2R,5R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)piperidine-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide;(R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-oxopiperidine-3-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-fluoropyridine-3-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1H-imidazole-5-carboxamide;N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide;(S)-N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-cyclopropyl-5-oxopyrrolidine-3-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-ethyl-6-oxopiperidine-3-carboxamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-N-(2-fluoroethyl)-3-hydroxypropanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxypropyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(4-hydroxycyclohexyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4r)-4-hydroxycyclohexyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4s)-4-hydroxycyclohexyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(3-hydroxypiperidin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxycyclopentyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)ethanone;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(3-(trifluoromethyl)piperazin-1-yl)propan-1-one;2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1-yl)-3-hydroxypropan-1-one;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methanesulfonyl-piperazine-1-carboxamide;1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)urea;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)piperazine-1-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-4,7-diazaspiro[2.59]octane-7-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethy)-4,7-diazaspiro[2.5]octane-7-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-(trifluoromethyl)piperazine-1-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-oxopiperazine-1-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-3-oxopiperazine-1-carboxamide;4-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-methylpiperazin-2-one;4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-(2-hydroxyethyl)piperazin-2-one;4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)piperazin-2-one;and(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)(3-(trifluoromethyl)piperazin-1-yl)methanone.6. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound having the structure of Formula (1), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier:

wherein: R¹ is a haloalkyl having 1-6 fluorine atoms; R² is C₁₋₆ alkyl,C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may be optionallysubstituted with halo, amino or hydroxyl groups; halo, cyano, nitro,(CR₂)_(k)OR⁷, (CR₂)_(k)O(CR₂)₁₋₄R⁷, (CR₂)_(k)SR⁷, (CR₂)_(k)NR⁹R¹⁰,(CR₂)_(k)C(O)O₀₋₁R⁷, OC(O)R⁷, (CR₂)_(k)C(S)R⁷, (CR₂)_(k)C(O)NR⁹R¹⁰,(CR₂)_(k)C(O)NR(CR₂)₀₋₆C(O)O₀₋₁R⁷, (CR₂)_(k)NRC(O)O₀₋₁R⁷,(CR₂)_(k)S(O)₁₋₂NR⁹R¹⁰, (CR₂)_(k)S(O)₁₋₂R⁸, (CR₂)_(k)NRS(O)₁₋₂R⁸ or(CR₂)_(k)R⁶; or any two adjacent R² groups together may form anoptionally substituted 5-8 membered carbocyclic, heterocyclic, aryl orheteroaryl ring; R³ is selected from the group consisting of

R⁹ and R¹⁰ are independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, each of which may be optionally substituted with halo, amino,hydroxyl, alkoxy, cyano, carboxyl or R⁶; (CR₂)_(k)CN, (CR₂)₁-₆NR⁷R⁷,(CR₂)₁₋₆OR⁷, (CR₂)_(k)C(O)O₀₋₁R⁷, (CR₂)_(k)C(O)NR⁷R⁷ or (CR₂)_(k—)R⁶; R⁶is an optionally substituted C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, or a 5-10membered heteroaryl or 5-7 membered heterocyclic ring; R⁷ and R⁸ areindependently (CR₂)_(k—)R⁶ or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl,each of which may be optionally substituted with halo, amino, amido, orhydroxyl, alkoxy, cyano, carboxyl or R⁶; or R⁷ is H; each R is H orC₁₋₆alkyl; each k is 0-6; and j and m are independently 0-4.
 7. Thepharmaceutical composition of claim 6, wherein the compound is selectedfrom the group consisting of:N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-methylpiperidine-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclol[3.1.0]hexane-2-carboxamide;(1S,2R,5R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclol[3.1.0]hexane-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)piperidine-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide;(R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-oxopiperidine-3-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-fluoropyridine-3-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1H-imidazole-5-carboxamide;N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide;(S)-N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-cyclopropyl-5-oxopyrrolidine-3-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-ethyl-6-oxopiperidine-3-carboxamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-N-(2-fluoroethyl)-3-hydroxypropanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxypropyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(4-hydroxycyclohexyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((lr,4r)-4-hydroxycyclohexyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4s)-4-hydroxycyclohexyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(3-hydroxypiperidin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxycyclopentyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)ethanone;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(3-(trifluoromethyl)piperazin-1-yl)propan-1-one;2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1 -yl)-3 -hydroxypropan- 1 -one; N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methanesulfonyl-piperazine-1-carboxamide;1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)urea;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxethyl)piperazine-1-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide;N-(5-(5-(4(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-4,7-diazaspiro[2.5]octane-7-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethy)-4,7-diazaspiro[2.5]octane-7-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-(trifluoromethyl)piperazine-1-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-oxopiperazine-1-carboxamide;N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-3-oxopiperazine-1-carboxamide;4-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-methylpiperazin-2-one;4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-(2-hydroxyethyl)piperazin-2-one;4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)piperazin-2-one; and(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)(3-(trifluoromethyl)piperazin-1-yl)methanone.